The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Social Media Editor Dr. Kristin Anderson.
“An oncolytic virus–delivered TGFβ inhibitor overcomes the immunosuppressive tumor microenvironment” by DePeaux et al
J Exp Med (2023)
Abstract:
While checkpoint blockade immunotherapies have widespread success, they rely on a responsive immune infiltrate; as such, treatments enhancing immune infiltration and preventing immunosuppression are of critical need. We previously generated αPD-1 resistant variants of the murine HNSCC model MEER. While entirely αPD-1 resistant, these tumors regress after single dose of oncolytic vaccinia virus (VV). We then generated a VV-resistant MEER line to dissect the immunologic features of sensitive and resistant tumors. While treatment of both tumor types induced immune infiltration and IFNγ, we found a defining feature of resistance was elevation of immunosuppressive cytokines like TGFβ, which blunted IFNγ signaling, especially in regulatory T cells. We engineered VV to express a genetically encoded TGFβRII inhibitor. Inhibitor-expressing VV produced regressions in resistant tumor models and showed impressive synergy with checkpoint blockade. Importantly, tumor-specific, viral delivery of TGFβ inhibition had no toxicities associated with systemic TGFβ/TGFβR inhibition. Our data suggest that aside from stimulating immune infiltration, oncolytic viruses are attractive means to deliver agents to limit immunosuppression in cancer.
Why this matters:
In this article, DePeaux and colleagues demonstrate that an oncolytic virus encoding a TGFbRII inhibitor can enhance immunotherapy efficacy in mouse models of checkpoint blockade and oncolytic virus-resistant head and neck squamous cell carcinoma and melanoma. They show that this effect is mediated by alleviating suppression from regulatory T cells in the tumor microenvironment. This research is valuable for the field because TGFb signaling in the tumor microenvironment has plagued the development of effective immunotherapies for solid tumors. Systemic TGFb/TFGbR inhibition has been associated with toxicities, and this tumor-targeting approach offers a targeted opportunity to address an immunosuppressive feature of solid tumors.
“The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC” by Javitt et al
Nat Cancer (2023)
Abstract:
Immunotherapy revolutionized treatment options in cancer, yet the mechanisms underlying resistance in many patients remain poorly understood. Cellular proteasomes have been implicated in modulating antitumor immunity by regulating antigen processing, antigen presentation, inflammatory signaling and immune cell activation. However, whether and how proteasome complex heterogeneity may affect tumor progression and the response to immunotherapy has not been systematically examined. Here, we show that proteasome complex composition varies substantially across cancers and impacts tumor-immune interactions and the tumor microenvironment. Through profiling of the degradation landscape of patient-derived non-small-cell lung carcinoma samples, we find that the proteasome regulator PSME4 is upregulated in tumors, alters proteasome activity, attenuates presented antigenic diversity and associates with lack of response to immunotherapy. Collectively, our approach affords a paradigm by which proteasome composition heterogeneity and function should be examined across cancer types and targeted in the context of precision oncology.
Why this matters: In this Nature Cancer article, Javitt and colleagues demonstrate that the presence of a particular proteasome regulatory cap, PSME4, reduces tumor antigen presentation by restricting immunopeptidome diversity, and this correlates with reduced T cell infiltration in lung cancer. I found this paper important for the immunotherapy community because it highlights another mechanism by which tumor cells can evade detection by antitumor T cells.
“Manipulating mitochondrial electron flow enhances tumor immunogenicity” by Mangalhara et al
Science (2023)
Abstract:
Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.
Why this matters:
Recently in Science, Mangalhara and colleagues demonstrated that modulating electron flow through the electron transport chain can alter antitumor immunity. They illustrate that blocking complex II (succinate dehydrogenase) by genetic knockout or chemical inhibition results in increased MHCI expression, immune cell infiltration, and enhanced tumor control. Their work revealed that elevated levels of succinate (and corresponding low levels of a-ketoglutarate) result in histone methylation and enhanced transcription of MHC and antigen processing and presentation genes. I found this paper intriguing because it highlighted another direct and important link between cellular metabolism and antitumor immunity.