Immune checkpoint blockade therapy (ICBT), which blocks negative immune-activating signals and maintains the antitumor response, has elicited a remarkable clinical response in certain cancer patients. However, intrinsic resistance (i.e., insensitivity of the tumors to therapy) remains a daunting challenge. The efficacy of ICBT is tightly modulated by the function of each step in the antitumor immunity cycle. Mechanistically, the number of mutations determines tumor immunogenicity. The properties of the tumor microenvironment control T-cell infiltration, distribution, and function in tumor tissues. Low tumor immunogenicity and a strong immunosuppressive tumor microenvironment cause significant intrinsic resistance to ICBT. With our evolving understanding of intrinsic resistance, people have successfully tested, in preclinical models, treatments targeting specific resistance mechanisms to sensitize ICBT-resistant tumors. Translation of those preclinical findings to the clinical arena will help generate personalized ICBT strategies that target tumor-specific resistance mechanisms. Progress in the new personalized ICBT strategies will expand the reach of immunotherapy to more cancer types, thus enabling more patients to benefit. Cancer Res; 77(4); 817–22. ©2017 AACR.

The use of chemotherapy, radiotherapy, and surgery dominated the cancer treatment field, at least until the elucidation of the molecular mechanisms that regulate cancer progression ushered in the second generation of treatment strategies: targeted therapy. However, tumors are communities of not only malignant cells but also surrounding stromal cells, particularly the tumor-infiltrating lymphocytes (TIL) that help remove tumor cells. With the rapid growth in our understanding of cancer immunology, immunotherapy now aims to eliminate tumors via improving the antitumor immune response of cytotoxic TILs in tumor tissue (rather than targeting tumor cells directly). Immunotherapy has profoundly changed the paradigm of cancer treatment; it has joined the ranks of chemotherapy, radiotherapy, surgery, and targeted therapy as a pillar of cancer treatment strategies.

Immune checkpoints are critical molecules that either turn up or turn down the T-cell–stimulatory signals of the immune response. Unlike the classic mAbs that target oncogenic pathways, such as HER2 to kill tumor cells, the mAbs of inhibitory immune checkpoints stimulate the functions of T cell. Since 2011, blockers of inhibitory immune checkpoints, such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), have been approved by the FDA to treat solid tumors, thanks to their exciting success in clinical trials. By inhibiting the immune checkpoints that suppress T-cell activation, immune checkpoint blockade therapy (ICBT) has resulted in a response rate as high as 40% in melanoma patients, with some durable effects (1, 2). However, in large-scale use in patients with solid tumors, ICBT remains ineffective, for two main reasons: adaptive resistance and intrinsic resistance. Adaptive resistance occurs rapidly after an initial clinical response; the process involves the changing of phenotypes in cancer cells and/or in the tumor microenvironment from sensitive to resistant (as recently reviewed by Ribas; ref. 3).

Intrinsic resistance is more common. This term refers to tumors that either fail to respond at all to ICBT or, even worse, react to ICBT by accelerating their progression. To enable more patients to benefit from ICBT, we urgently need to understand the mechanisms of intrinsic resistance and to find combination treatment strategies based on molecular processes to overcome it. In this review, we explored the basic biology of immune checkpoints in cancer, our current understanding of the mechanisms of intrinsic resistance to ICBT, and, in particular, novel strategies to overcome intrinsic resistance by targeting those mechanisms.

Immune checkpoints control the balance of costimulatory and coinhibitory signals, which play essential roles in regulating the amplitude and duration of T-cell responses. Coinhibitory immune checkpoints are critical for avoiding autoimmunity. However, they also restrict the duration and robustness of antitumor immunity. Clinical success with blocking CTLA-4 and PD-1, the first-generation coinhibitory checkpoint receptors to be targeted, has opened the way to strategies for blocking inhibitory immune checkpoints.

PD-1, a cell surface receptor that belongs to the immunoglobulin superfamily, is mainly expressed on T cells that are activated by T-cell receptor (TCR) engagement (4). PD-1 expression requires transcriptional activation and takes about 12 hours. Once stimulated, PD-1 directly inhibits TCR-mediated downstream signaling and increases T-cell migration within tissues. The constantly moving T cells have only a limited time to survey the surface of interacting cells for the presence of the cognate peptide–MHC complex, so T cells can “pass over” target cells that have a lower peptide–MHC complex level (5). PD-1 binds to two ligands: PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273). The major stimulator of PD-L1 expression, which is primarily found on hematopoietic and epithelia cells, is inflammatory cytokine IFNγ produced by activated T cells and by natural killer (NK) cells (4). In contrast to the wide expression range of PD-L1, PD-L2 expression is more selective. Induced by IL4 rather than by IFNγ, PD-L2 is expressed on activated dendritic cells (DC) and macrophages (4).

Unlike PD-1, which dampens T-cell activation, CD28 is expressed in T cells to enhance TCR signaling when TCR is engaged by the peptide–MHC complex (6). CD28 is the receptor of CD80 (B7.1), CD86 (B7.2), and inducible costimulatory (ICOS)-L proteins, all of which are expressed in the antigen-presenting cells (APC), such as DCs and monocytes (6). As a feedback inhibitory mechanism of CD28-enhanced T-cell activation, CTLA-4 is expressed in activated T cells that already express CD28; it shares both CD80 and CD86 as its ligands, along with CD28, and shows a higher affinity for both ligands than for CD28 (6). Therefore, CTLA-4 expression on activated T cells dampens CD28 costimulation by competing or depleting ligands of the CD28 signaling pathway. In addition, biochemical evidence has suggested that CTLA-4 also recruits phosphatases to attenuate the TCR signal. Activation of two phosphatases, PP2A and SHP2, is critical in counteracting both tyrosine and serine/threonine kinase signals induced by TCR and CD28 (6). Moreover, CTLA-4 induces T-cell motility and overrules the TCR-induced stop signal required for stable conjugate formation between T cells and APCs (7). This mechanism leads to fewer contact periods between T cells and APCs, resulting in decreased T-cell priming and proliferation.

In addition to what is mentioned above, some cancers have a signature of T-cell–suppressive mechanisms that include not only the PD-1 pathway and the CTLA-4 system but also other inhibitory pathways, such as indoleamine 2,3-dioxygenase (IDO), OX40 (CD134), 4-1BB (CD137), LAG3, and P-selectin glycoprotein ligand-1 (PSGL-1), which have been tested in preclinical models and are now entering clinical trials (8).

For an antitumor immune response to kill cancer cells efficiently, a series of stepwise events must be initiated and then iteratively expand (Fig. 1A). The whole antitumor immunity cycle can broadly be divided into three major stages: (i) initiation of antitumor immunity (antigen release, presentation, and T-cell priming); (ii) cancer-specific cytotoxic T lymphocytes (CTL) infiltration (trafficking of CTLs, followed by infiltration of CTLs into the tumor microenvironment, and survival of CTLs in the tumor microenvironment); and (iii) killing of cancer cells (recognizing and killing of cancer cells; ref. 9). The elimination of cancer by ICBT primary relies on activating naïve T cells (anti-CTLA-4) or CTLs in tumors (anti-PD-1/PD-L1); however, it is tightly regulated by other steps. Therefore, an abnormality in any step can directly lead to intrinsic resistance to ICBT.

Figure 1.

A, Basis of antitumor immunity. The antitumor immunity can be broadly divided into three major stages. The process involving seven key steps begins with the release of tumor antigens and ends with the elimination of cancer cells. The primary cell types involved in each of these seven steps are described. B and C, Schematic representation of cancer treatment responses observed with various therapeutic strategies. Cancer immunotherapy demonstrates a unique feature of long-term tumor control. It is expected that more patients will respond to the proposed new combinatorial and personalized immunotherapy with a better clinical outcome, in comparison with traditional therapies.

Figure 1.

A, Basis of antitumor immunity. The antitumor immunity can be broadly divided into three major stages. The process involving seven key steps begins with the release of tumor antigens and ends with the elimination of cancer cells. The primary cell types involved in each of these seven steps are described. B and C, Schematic representation of cancer treatment responses observed with various therapeutic strategies. Cancer immunotherapy demonstrates a unique feature of long-term tumor control. It is expected that more patients will respond to the proposed new combinatorial and personalized immunotherapy with a better clinical outcome, in comparison with traditional therapies.

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Tumor cell mutations and tumor immunogenicity

By its very nature, cancer involves the accumulation of mutations in the genome of transformed cells, resulting in abnormal phenotypes in those cells. During the process of T-cell maturation, T cells that recognize autoantigen are cleared away; therefore, the tumor antigens encoded by mutated genes (mutations that are not seen in healthy individuals) trigger a strong antitumor immune response. The individual features of cancer cells determine the intensity of the initial step of antitumor immunity: tumor antigen release. The mutation burden varies widely among different types of tumors, ranging from as few as 10 mutations to thousands (10). Recent studies found that tumors that have heavier mutation burden would be more likely to be seen by the immune system and would response better to ICBT. For example, in genome-wide studies of non–small cell lung cancer (NSCLC) and melanoma (the two cancers that have so far demonstrated the best response to ICBT), the mutation burden and the neoantigen load closely correlated with a better clinical outcome (11, 12). Defects in DNA repair machinery lead to high microsatellite instability in tumor cells and thus potentially to more neoantigens. Such tumors have consistently been associated with a better clinical outcome and with a durable benefit from ICBT (13). Moreover, T cells that recognize clonal neoantigens have been found in NSCLC patients with a durable clinical benefit from ICBT, directly supporting the notion that neoantigens encoded by mutated genes could be immunogenic and thus could lead to a better response to ICBT (12).

Among the thousands of mutations in cancers, a few are driver mutations in oncogenes and in tumor suppressor genes (TSG). Driver mutations play a critical role in initiating tumor development. Recent reports have helped elucidate the roles of specific oncogenes and TSGs in modeling the immunogenic tumor microenvironment. For example, inactivation of PTEN, a TSG in melanoma, correlated with decreased T-cell infiltration in tumor tissue and with inferior outcomes after anti-PD-1 therapy (14). Knockout of PTEN in tumors increased the expression of immunosuppressive cytokines (14). Besides TSGs, the oncogene MYC also regulates antitumor immunity. MYC enhances CD47 and PD-L1 expression via coding for a transcription factor that binds directly to their promoters (15). In vitro and in vivo inactivation of the MYC oncogene resulted in a rapid downregulation of CD47 and PD-L1 in T cells in both mRNA and protein (15). In short, recent findings suggested very specific roles of different oncogenes and TSGs in resistance to ICBT.

Clearly, tumor immunogenicity and the CTL-rich tumor microenvironment are the basis of ICBT, which is modulated in multiple possible ways by genome mutations. Although it is still not possible to improve tumor immunogenicity by specifically editing a tumor cell's genome, the recent findings at least offer a rationale for combining certain regimens in a manner that might enhance tumor immunogenicity with ICBT in clinical practice. In terms of biomarker, the findings support the possibility of using whole-exome sequencing and neoepitope predictions as novel methods to identify, in advance, which patients will respond to ICBT. Future investigations in these aspects might lead to promising strategies in overcoming ICBT-intrinsic resistance.

Tumor microenvironment and immune exclusion

In the antitumor immunity cycle, the tumor microenvironment mainly controls infiltration by CTLs and their function in killing cancer cells. Dynamic interactions exist between CTLs and the immunosuppressive tumor microenvironment components to tip the balance from immune reactivity to immunosuppression. The mechanisms related to tumor microenvironment components caused ICBT-intrinsic resistance are summarized below.

T-cell infiltration.

After cancer-specific T cells are primed in the tumor-draining lymph nodes, the cells move through the vascular system to the tumor site. Successful T-cell infiltration not only relies on appropriate chemokine attraction, but also controlled by dysfunctional tumor vasculature. By comparing T-cell–rich and T-cell–poor tumors, researchers have found that the apoptosis-inducing Fas ligand (FasL), which is expressed in tumor vasculature, negatively controls tumor-infiltrating CD8+ T cells (16). Tumors with high levels of endothelial FasL tend to have few CD8+ T cells but an abundant number of regulatory T cells (Treg), which are protected from FasL-mediated cell death (16). Multiple factors other than FasL, such as endothelin B receptor (ETBR), are also involved in vasculature-controlled T-cell infiltration (17). In preclinical pharmacologic models, inhibition of ETBR substantially increased T-cell adhesion to endothelial cells, resulting in enhanced T-cell function (17).

Continued functionality of T cells.

Infiltration of T cells is necessary but not sufficient in responding to ICBT. For effective tumor killing, T cells must be able to maintain functionality while sitting and migrating in the tumor microenvironment. Expression of immune checkpoints is the internal mechanism for regulating T-cell function, but interactions between T cells and the tumor microenvironment also matter. In tumor microenvironment, the normal myeloid cell differentiation pathways are altered, generating a large number of myeloid-derived suppressor cells (MDSC; ref. 18). MDSCs suppress T-cell replication and function in the tumor microenvironment with multiple mechanisms, such as generating oxidative stress, depleting required nutrients of lymphocytes, and enhancing immunosuppression of Tregs (reviewed by Gabrilovich and colleagues; ref. 18). A diminished supply of energy creates another bottleneck that limits effector T-cell functionality in the tumor microenvironment. Because of the abnormal vasculature of cancer cells and their high rate of glycolysis, T cells are in a microenvironment that lacks glucose influx. The absence of glucose inhibits aerobic glycolysis in effector T cells, leading to compromised production of cytotoxic effector IFNγ (19).

Spatial distribution of T cells.

Increased numbers of infiltrated and functional cancer-specific T cells will be of little importance if T cells never have a chance to reach the vicinity of cancer cells. Recently, the impact on immune regulation of cancer-associated fibroblasts (CAF) has become clearer, especially the role of fibroblast activation protein-α (FAP)-positive CAFs in T-cell distribution in tumor tissues (20). CAFs restrict T cells from tumor cells in two ways. First, the extracellular matrix that they produce forms a physical barrier to prevent T-cell migration to tumor regions (21). Second, experimental studies have shown that FAP+ CAFs block T cells from reaching tumor cells by secreting CXCL12, which coats cancer cells with a biochemical barrier and by recruiting MDSCs into tumor microenvironment (20, 22). The detailed mechanisms are not yet clear, but, at least in preclinical pancreatic cancer models, targeting the FAP+ CAF-dominated CXCL12/CXCR4 axis shows promise in reversing resistance to ICBT (20).

The significance of investigating ICBT-intrinsic resistance mechanisms is generating novel strategies to improve the efficacy of ICBT by targeting specific intrinsic resistance pathways. In an effort to achieve a better clinical outcome, multiple strategies targeting different mechanisms of intrinsic resistance are now being proposed and tested in both preclinical models and clinical trials, as highlighted below.

Increasing tumor immunogenicity by chemotherapy and radiotherapy

Most cancer patients undergo chemotherapy and/or radiotherapy with the primary goal of controlling local cancer and/or metastasis. Chemotherapy is considered to be immunosuppressive, given its myelosuppression. Yet, certain chemotherapeutic agents, such as oxaliplatin, have been proven to enhance antitumor T-cell immunity by inducing immunogenic cell death (23). Tumor cell death induced by radiotherapy usually releases tumor-derived antigen as well as danger signals that could be captured for triggering antitumor immunity. In addition, radiotherapy increases the expression of MHC molecules, immune-activating chemokines and cytokines, and enhances the diversity of the TCR repertoire of intratumoral T cells (24, 25). In preclinical models, the synergistic effects of certain types of chemotherapy and radiotherapy with ICBT have been observed, indicating the great potential of this combination treatment to avert intrinsic resistance to ICBT (23, 24).

Targeting APCs to improve antigen presentation and T-cell priming

The function of APCs in antitumor immunity is to transfer tumor antigens to tumor-draining lymph nodes for tumor-specific CD8+ T-cell priming. In melanoma, CD103+ DCs are the only APCs that have such a function (26). In melanoma mouse models, administration of the growth factor FLT3L and poly I:C has expanded and activated CD103+ DC progenitors in the tumor, thereby reversing anti-PD-L1 resistance (26). Besides expanding DCs by growth factors, using a DC-based vaccine can also increase the breadth and diversity of neoantigen-specific T cells (27). Thus, using a DC-based vaccine to overcome ICBT would also be promising.

Targeting CAFs to improve T-cell infiltration

CAFs have been shown to play a major role in preventing T cells away from tumor cells in the tumor microenvironment. In pancreatic adenocarcinoma, stroma takes up the majority of tumor tissue and does not respond to ICBT. However, depletion of FAP+ CAF-mediated CXCL12/CXCR4 axis improved the number of T cells in the tumor microenvironment and shortened the distance between T cells and tumor cells, thereby enhancing antitumor effects of ICBT in spontaneous pancreatic adenocarcinoma mouse models that fully recapitulate human disease (20). Inhibiting another tumor stromal factor, focal adhesion kinase, also increased T-cell infiltration by depleting the desmoplastic and immunosuppressive pancreatic adenocarcinoma microenvironment and rendering tumors responsive to ICBT (28). Taken together, these exciting findings suggest that targeting CAFs and/or desmoplasia might help overcome intrinsic resistance to ICBT, at least in tumor stroma–enriched cancers like pancreatic adenocarcinoma.

Targeting MDSCs to release immunosuppression

Given the extensive impact of MDSCs on T-cell suppression, targeting them has been widely tested in preclinical models as a strategy to overcome resistance to ICBT. In cancer-bearing mouse models, a strategy that combined targeting MDSCs by epigenetic modulating or by signaling pathway–targeting drugs that primarily deplete MDSCs markedly improved the response to ICBT (29). Another strategy is promoting the maturation of MDSCs into APCs in the tumor microenvironment. CD40 agonist antibodies promote APC maturation and enhance macrophage tumoricidal activity (30). In a preclinical model of pancreatic cancer, administration of CD40 antibodies drove systemic APC maturation, expanded the number of memory T cells, and increased CD8+ T-cell infiltration (30). CD40 antibodies with a PD-L1 blockade (as compared with a PD-L1 blockade alone) enhanced antitumor immunity and improved overall survival (30).

Attempts to break resistance to ICBT by boosting specific steps in the antitumor immunity cycle represent a fast-growing field that is entering the arena of future antitumor treatment. It is important to keep in mind that, even though strategies have been classified by their major role in modulating antitumor immunity, a given strategy could have multiple roles in different aspects of the antitumor immunity cycle.

The past decades have seen substantial advances in our understanding of immune checkpoint activity and in its clinical success, but because of intrinsic resistance, only a small proportion of patients have benefited so far from ICBT. Recent studies have revealed multiple mechanisms of intrinsic resistance and potential ways to overcome it.

However, key challenges remain before we can translate our findings from bench to bedside. First, the roles of APCs in modulating ICBT-intrinsic resistance remain unclear. For example, although APCs link tumor antigen release and T-cell activation, few studies have noted whether or not APCs were dysfunctional in cancer patients who did not respond to ICBT, so we do not know whether dysfunction of APCs is a significant mechanism of intrinsic resistance. Second, targeted treatments for overcoming resistance to ICBT rely on the precise classification of resistant mechanisms upon diagnosis. Although genome sequencing studies have suggested that the number of mutations might predict response to ICBT, the enormous costs of exome sequencing make large-scale genome-wide diagnosis cost-prohibitive. Therefore, identifying the key mutations that elicit high tumor immunogenicity is crucial for predicting intrinsic resistance to ICBT and for fine-tuning treatments. Third, the therapeutic compounds and doses used in preclinical studies are not yet approved for human use. Finding safe and efficient inhibitors of each mechanism of resistance to ICBT is a prerequisite to translating preclinical findings to the clinical arena. Finally, the current preclinical studies mainly focus on modifying the antitumor immune response in tumor site. However, the roles of systemic therapies on the whole immune system in releasing intrinsic ICBT resistance are underexamined. It is worth noting that in clinical settings, before taking ICBT, patients may get standard treatments that potentially impair the immune system. This could result in ICBT failure due to systemic immunosuppression. Therefore, the key questions to be further investigated are whether systemic therapies are also helpful to overcome intrinsic ICBT resistance, and how to balance their effects in enhancing ICBT and causing potential autoimmune diseases.

Current strategies to overcome intrinsic resistance include combining ICBT with conventional treatments (like chemotherapy and radiotherapy), as well as combining immune checkpoint blockades with different targets (anti-CTLA-4 and anti-PD-1/PD-L1). However, without knowing the specific mechanisms, the current uniform combinations are less effective and could be more toxic. For example, anti-CTLA-4 and anti-PD-1 combination in untreated melanoma caused higher rate of treatment-related adverse events of grade 3 or 4 due to strong nonspecific immune activation (1). Understanding the detailed mechanisms of intrinsic resistance to ICBT will help us develop the next generation of effective, nontoxic strategies. In light of ongoing efforts to translate the exciting laboratory findings to clinical trials, we are able to propose the novel ICBT strategies as ICBT sensitivity prediction + personalized immune checkpoint blockades sensitizers + proper immune checkpoint blockades. By the novel personalized ICBT strategies, we are confident that more cancer patients will benefit from ICBT (Fig. 1B and C), making it an exciting time in defeating cancers.

No potential conflicts of interest were disclosed.

We thank Drs. Lihua Li and Anne Sarver for helpful discussions and Leeanne Dongses and Dr. Mary Knatterud for assisting in manuscript preparation. Because of space restrictions, we cannot cite many other significant contributions made by numerous researchers and laboratories in this potentially important and rapidly progressing field.

S. Subramanian was supported by research grants funded by the American Cancer Society (grant RSG 13-381-01-RMC), the Zach Sobiech Osteosarcoma Fund, and the Karen Wyckoff Rein in Sarcoma Foundation. X. Zhao was supported by a University of Minnesota Department of Surgery research fellowship.

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