Reviving cancer immune surveillance with CD4 T cell help

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Abstract The immune system is capable of eliminating advanced malignant tumors, yet cancer immunotherapy success has been limited to a subset of cancer types. Conventional CD4, or `helper', T cells play an integral role in orchestrating immune responses, and can potentiate the function of antitumor immunity: both via activation and potentiation of antigen presenting cell function and antitumor CD8 T cells. My postdoctoral work demonstrated that reactivating childhood vaccine-specific CD4 T cells after intratumor injection of recall antigen (e.g. polio capsid or tetanus toxoid), mediates antitumor efficacy and causes both innate and adaptive inflammation within tumors. The antitumor efficacy of intratumor recall responses were partially dependent upon CD8 T cells, and coincided with infiltration of activated granulocytic macrophages with phenotypes distinct from tumor associated macrophages after direct innate stimulation with Poly IC. Thus, inducing CD4 T cell recall represents a novel therapeutic opportunity, with a distinct mode of inflammatory and antitumor potential. We hypothesize that intratumor childhood vaccine-specific CD4+ T cell recall responses instigate distinct and durable inflammatory reprograming of myeloid cells to potentiate antitumor CD8+ T cell function and mediate antitumor efficacy. To test this hypothesis, we will define reprogramming of innate immunity after triggering intratumor recall responses and determine its role in mediating antitumor efficacy (Aim 1) and test if polio vaccine-specific CD4+ T cell recall responses `help' antitumor CD8+ T cells (Aim 2). These analyses will inform clinically actionable routes to develop recall antigen-based therapies that enlist CD4 T cell help within tumors (the goal of the independent, R00 phase). The clinical translation of these findings will be informed by identifying therapeutic strategies, such as combined innate pattern recognition receptor agonist therapy, that may synergize with recall antigens in mediating systemic antitumor efficacy; as well as identifying more targeted molecular routes to recapitulate CD4 T cell help in tumors therapeutically (Aim 3). The K99 phase of this work will be mentored by several distinguished experts in tumor immunobiology and cancer immunotherapy: including Drs. Darell Bigner (primary Mentor, cancer immunotherapy of brain tumors), Simon Gregory (computational expert), Qi Jing-Li (T cell biologist using transcriptome analyses to gauge T cell function), Amy Heimberger (tumor associated myeloid cell expert who has previously applied transcriptome analyses to define activation/suppressive features of tumor associated myeloid cells), and James Herndon II (biostatistical support). This proposal will enable clinical translation of recall antigens to cancer patients and will seed a research program that leverages the potent immune-stimulating effects of CD4+ T cell help to develop novel cancer therapies.