A Sweet Approach to Heat Up Cancer Response to Immunotherapy

The benefits of cancer immunotherapy have been significant for some immunogenic cancers including melanoma and mismatch repair–deficient gastrointestinal cancer; however, only a small proportion of people with other solid cancers show a favorable response to currently used immune checkpoint inhibitors. The cancer immunity cycle (1) provides a rationale for understanding response to immunotherapy by describing several barriers that must be overcome for host immunity to be able to mount an effective anticancer response. From the cycle, three broad cancer immune phenotypes (2) were derived that are defined by where the immunity cycle is interrupted, called immune desert (cold tumors with low immune infiltrate), inflamed (hot tumors with significant immune cell infiltrate), and inflamed excluded (a subtle variation of the inflamed that is defined by the location of immune cells within the tumor tissue). These immune phenotypes appear to be a feature of several cancer types, and the immune cold phenotype, which is the least responsive to immunotherapy, may be present in more than 50% of cases for some cancers (3). Cold tumors result from defective immune priming and immunologic ignorance (lack of antigens and antigen presentation). Immunotherapeutic approaches to treat patients with cold tumors include vaccinations, redirection of immune cells by the use of genetic manipulation (transduction of T-cell receptors or chimeric antigen receptors), and induction of immunogenic cell death. To understand how immune cold tumors can be “heated” up, it is important to determine the exact mechanisms that lead to cold tumors.

In this issue of Cancer Discovery, Song and colleagues (4) have investigated the B7-H4 immune checkpoint molecule that associates with poor outcomes in several cancer types though inhibition of TCR-mediated T-cell proliferation and cell-cycle regulation (5). Through interrogation of publicly available datasets of breast cancer, the authors found B7-H4 was associated with immune cold tumors. Analysis of breast cancer cell lines revealed B7-H4 to be expressed by malignant cells with low/no PD-L1 expression (and vice versa), and within breast cancer tissues the expression of B4-H7 negatively associates with CD3 cell infiltrate and PD-L1 expression. Using preclinical murine models of breast cancer, the authors show that degradation of B7-H4 leads to immunogenic cell death through expression of several “eat me” molecules, and improved cytotoxic immune cell infiltration that when combined with anti–PD-1 immunotherapy further reduces tumor growth. In other words, inhibition of B4-H7 expression on malignant cells heated up a cold tumor to a hot and inflamed phenotype that is potentially responsive to classic immune checkpoint blockade with PD-1 or CTLA4 inhibitors.

B4-H7 is degraded naturally via ubiquitylation. However, the authors show that in malignant disease B4-H7 expression is stabilized by the addition of N-glycans at several asparagine residues that block access to sites of ubiquitylation. Glycosylation is readily targetable in situ through the use of naturally occurring glycosidase enzymes, or chemical methods which have been more extensively explored for another family of checkpoint molecules called SIGLECs, which are also showing efficacy in preclinical models (6). Here the authors made use of a small-molecule oligosaccharyltransferase inhibitor, NGI-1 (7), which inhibits the addition of N-glycans to B4-H7. NGI-1 was used as part of a triple-therapy approach with a doxorubicin derivative that enhanced immunogenic cell death and anti–PD-1 to afford improved survival in preclinical mouse models (Fig. 1).

This excellent study provides another example of the way glycosylation can influence cancer progression and antitumor immunity. Glycans can for example act as a stabilizer or enhancer of biological signaling that malignant cells use to sculpt their microenvironment to escape host immunity and therapy. Other similar examples of how N-glycosylation is utilized by malignant cells include resistance to cetuximab (8) and mediation of immune escape in colorectal cancer (9). The presentation of glycans decorated with sialic acids (sialoglycans) has been also associated with an immunosuppressive tumor microenvironment (10). Sialoglycans can engage immune-modulatory SIGLEC receptors that inhibit both innate and adaptive immune cells. A first antibody targeting SIGLEC15 is currently in early clinical trials (NCT03665285). Galectins, which recognize galactose-containing glycans, can also engage immune checkpoints including TIM3 and LAG3 (10), which are currently targeted in clinical trials by blocking antibodies.

The clinical efficacy of targeting B7-H4 has not yet been established. There is currently one multicenter early phase I trial investigating an anti-B7H4 antibody in combination with pembrolizumab in several cancer types including breast cancer (NCT03514121), which has not yet released any results. Although heating up a tumor to an inflamed phenotype appears to improve therapy response rates, the cancer immunity cycle predicts several other barriers may need to be overcome. In particular, the inflamed excluded phenotype, which may comprise up to 50% of cases for some cancers (3), is defined by the location of the immune infiltrate being out of contact with malignant cells, and these tumors remain unresponsive to therapy (2). This would suggest that the location of the resulting inflammation will become more important to consider as we get better at heating up tumors using strategies such as the one proposed here by Song and colleagues.

H. Läubli reports grants from Palleon Pharmaceuticals, Bristol Myers Squibb, Swiss National Science Foundation, Krebsliga Beider Basel, Schoenemakers Foundation, and Goldschmidt-Jacobson Foundation during the conduct of the study; and personal fees from Limmatech Biologics and MSD outside the submitted work. No potential conflicts of interest were disclosed by the other author.