Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Project Summary Many cancer patients derive little to no benefit from currently available immunotherapy options. Responding patients also commonly develop acquired resistance to these immunotherapeutic agents. It is therefore evident that novel strategies are necessary to improve immunotherapy efficacy and extend the benefit of immunotherapy to a broader population of cancer patients. We have identified a tumor-intrinsic NLRP3 inflammasome pathway that plays an important role in the development of acquired resistance to immunotherapy in a variety of cancer types. In addition to mechanistically characterizing the role of this pathway in driving the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment and potently suppressing cytolytic T cell activity, this work has also demonstrated pharmacologic NLRP3 inhibition to augment anti-PD-1 efficacy in an autochthonous model of melanoma. Finally, this work has demonstrated that patients harboring melanomas that are genetically amplified for NLRP3 and exhibit enhanced NLRP3 inflammasome activity to also be resistant to anti-PD-1 immunotherapy in both the stage III and stage IV settings. Prior studies by others have demonstrated that tumor-mediated regulation of the MHC class I antigen processing and presentation is a key factor in determining responses to various immunotherapy modalities. While conducting our studies, we have also found that NLRP3 activation inhibits the expression of NLRC5, the class I transactivator, thus resulting in the downregulation of MHC class I expression in tumor cells. To date, our studies have shown that NLRP3 undergoes nuclear translocation in tumor cells upon activation and that NLRC5 suppression occurs in a non-inflammasome-dependent manner that can be reversed using a NLRP3- targeted inhibitor. As our data now suggests that the tumor NLRP3 inflammasome regulates both PMN-MDSC accumulation in tumors as well as the expression of various members of the MHC class I pathway, pharmacologic targeting of the NLRP3 inflammasome is quite attractive as a strategy to overcome anti-PD-1 resistance. However, concerns exist regarding systemic NLRP3 inhibition possibly blunting anti-tumor immunity by interfering with IL-18 release by various myeloid cell populations. Based on these prior findings, we now propose to conduct studies to characterize the underlying molecular mechanism for NLRP3-mediated inhibition of NLRC5 and its downstream MHC class I targets. This work will be coupled with the execution of CRISPR flow cytometry-based screens to identify tumor-restricted positive regulators of the NLRP3 signaling pathway. This work promises to lead to the development of novel pharmacologic targets capable of optimizing clinical responses to anti-PD-1 while expanding immunotherapy efficacy to traditionally refractory tumor types.