Immunotherapy is beneficial to only a subset of patients for reasons not yet fully understood. A new predictive algorithm identifies MHC-II neoantigens important for induction of CD8+ T-cell antitumor responses. Tumors need to coexpress both MHC-I and MHC-II neoantigens for optimal efficacy of immune checkpoint therapy and neoantigen-specific cancer vaccines leading to elimination of tumors in preclinical models (including ones that lack MHC-II). Thus, CD4+ and CD8+ T-cell responses in both the lymph node and tumor microenvironment are key to successful immunotherapy treatment.

Alspach E, …, Schreiber RD. Nature 2019 Oct;574:696–701.


Boosting T-cell metabolism (modified from moritz320 via Pixabay)

Responses to oncolytic viruses are limited by immunosuppressive tumor microenvironments (TMEs). Oncolytic vaccinia virus (OVV) slightly delays tumor growth by increasing accumulation of non-exhausted, yet metabolically deficient, CD8+ T cells recruited to the TME. Leptin revitalizes the metabolism of CD8+ T cells, resulting in T cell–mediated delays in tumor growth. Leptin-producing OVV improves the efficacy of OVV therapy by increasing functional, memory CD8+ T cells, inducing long-term antitumor immunity.

Rivadeneira DB, …, Delgoffe GM. Immunity 2019 Sep;51:548–60.e4.


The relationship between tumor clonal heterogeneity and T-cell clonal expansion is controversial. Wolf et al. examine melanoma in a controlled system in which intratumoral heterogeneity and immunity are compared independent of mutational burden, revealing complex relationships between tumor clonal heterogeneity, mutational burden, and antitumor response. Joshi et al. track the T-cell repertoire in patients with non–small cell lung cancer (NSCLC). The expansion of TCR clones and their diversity and relatedness reflect the local diversity of mutations at any one NSCLC tumor site. Blood obtained at the time of tumor resection is informative for tracking and monitoring relevant neoepitope-specific T cells.

Wolf Y, …, Samuels Y. Cell 2019 Sep;179:219–35.

Joshi K, …, Chain B. Nat Med 2019 Oct;25:1549–59.


CRISPR technology can be used to boost antitumor responses. Wang et al. developed MAEGI (multiplexed activation of endogenous genes as an immunotherapy) as a versatile and scalable treatment modality to fight cancer. This strategy capitalizes on CRISPR activation (CRISPRa) using inactive Cas9 to increase expression of specific endogenous tumor genes that are presented as tumor antigens. When MAEGI is delivered in vivo via an adeno-associated virus, antitumor responses were enhanced in both prophylactic and therapeutic models. This strategy thus has the potential to complement current treatment strategies.

Wang G, …, Chen S. Nat Immunol 2019 Oct;20:1494–505.


Specific inhibition of the driver mutation KRASG12C has been limited by its high affinity for GTP/GDP and the lack of a clear binding pocket. Two inhibitors, MRTX849 by Hallin et al. and AMG 510 by Canon et al., have been developed that covalently bind the cysteine mutation and block KRAS signaling (ERK and S6), subsequently delaying the growth of various KRASG12C -driven tumor models and inducing partial responses in lung cancer patients. The activity of the KRAS inhibitors can be enhanced by concurrent administration of RTK, SHP2, mTOR, MEK, PD-1, and CDK4/6 inhibitors, and KRAS inhibition can potentially lead to enhanced antitumor immunity and improved responses to checkpoint blockade.

Hallin J, …, Christensen JG. Cancer Discov 2019 Oct 28. DOI: 10.1158/2159-8290.CD-19-1167.

Canon J, …, Lipford JR. Nature 2019 Nov;575:217–23.


The complement system has emerged as an important component of the TME and tumor promotion. Fungi are found in pancreatic tumors, but the community of fungi in pancreatic tumors differs from that found in gut and normal pancreas. Tumors express a mannose-binding lectin that is cross-linked by fungi glycans to activate the complement cascade. Tumors also express the C3aR, and both the lectin and the C3aR are required for fungal-induced progression.

Aykut B, …, Miller G. Nature 2019 Oct;574:264–7.