Potentiating chemotherapy with polyfunctional CD4 effector T cells

Conventional chemotherapy can effectively treat the symptom of cancer initially, but its efficacy is often compromised by late tumor relapse. The recent revelation that certain chemotherapeutic agents have immunostimulatory effects drives a growing interest in combining chemotherapy and immunotherapy for synergistic antitumor effects and improved clinical outcomes. We recently reported that CD4 T-cell adoptive transfer following chemotherapy with Cyclophosphamide (Cy) gives rise to polyfunctional CD4 effector T cells that exhibit robust antitumor effect against established lymphomas. In preliminary studies, we show that these CD4 effector T cells act as critical 'gatekeepers' of the post-chemotherapy host immunity, by eliciting optimal functions of CD8 T cells and dendritic cells, and intensifying the chemotherapy-induced inflammatory milieu. However, CD4 effector T cells are subject to tolerization in the face of residual tumors and prolonged inflammation, leading to tumor re-regrowth. The goal of this project is to understand the dynamic mutual interaction between chemotherapy-induced inflammation and tumor-reactive CD4 effector T cells. Our central hypothesis is that a combined chemo-immunotherapy can be curative if tumor-reactive CD4 T cells are generated, and their polyfunctional effector state is sustained. Our objective is to develop clinically-applicable strategies to obtain tumor-reactive polyclonal CD4 effector T cells for chemoimmunotherapy, and avert CD4 T-cell tolerance by modulating the therapy-induced inflammatory milieu. We will accomplish this by pursuing two integrated specific aims. In aim 1, we will dissect the dynamic interaction between tumor-specific CD4 effector T cells and inflammation, and determine the efficacy of inflammation-modulating regimens. In aim 2, we will develop and optimize clinically-applicable strategies to obtain and expand vaccine-primed polyclonal tumor-reactive CD4 effector T cells, and use these cells in combination with chemotherapy and inflammation-modulating regimens to achieve durable antitumor effect. Successful completion of this project will lead to new insights and strategies to improve existing treatment modalities, and provide mechanistic guidance for the design and implementation of effective chemoimmunotherapies for various cancers.