91ΒιΆΉ

Reversing tumor-specific CD4+ T-cell tolerance to control relapse after chemotherapy

Using a mouse model of B-cell lymphoma, we reported that tumor antigen-specific CD4+ T cells undergo aberrant differentiation in the tumor setting, acquiring a dysfunctional phenotype and/or immunosuppressive activities. Certain widely-used chemotherapeutic agents, with cyclophosphamide as an example, can reprogram the tumor microenvironment from tolerogenic to immunogenic, thereby promoting the effector differentiation and clonally expansion of tumor-specific CD4+ T cells. These polyfunctional CD4+ effector cells in turn act as the β€œgatekeeper” of the host antitumor immunity, and their functional status critically determines the outcome between eradication and regrowth of the residual tumors. Our studies include identifying and characterizing novel CD4+ T cell-potentiating chemotherapeutic agents, elucidating the mechanisms by which CD4+ effector cells activate other tumor-reactive immune cells, revealing the transcriptomic and epigenetic landscapes dictating CD4+ T cell polyfunctionality. Findings from these studies will provide mechanistic basis for the design of more effective chemo-immunotherapy strategies that capitalize on the therapeutic potential of CD4+ T cells.

Chemotherapy-induced MDSCs and antitumor immunity

Tumor recurrence remains a major problem for patients with cancer. With the recent advances in immune-based therapeutic strategies, there is growing interest to synergistically combine immunotherapy with conventional chemotherapy to achieve durable antitumor effects. In some cases, chemotherapy-induced myeloid suppressor cells represent a critical obstacle to this goal. We recently reported that certain standard-of-care chemotherapeutic agents, including cyclophosphamide, melphalan and doxorubicin, can induce the expansion of immunosuppressive monocytic myeloid cells. We showed that selective depletion of chemotherapy-induced inflammatory monocytes following chemo-immunotherapy significantly improved long-term survival, providing evidence that therapy-induced monocytes contribute to tumor immune evasion and relapse. Our results suggest that the net impact of chemotherapy on tumor immunity is a dynamic balancing act between its two opposing immunomodulatory effects. Thus, targeting therapy-induced myeloid suppressor cells will allow robust response to immunotherapies in the post-chemotherapy window, thereby tilting the balance toward a durable therapeutic outcome.

Exploiting the immunomodulatory effects of sulindac and novel non-COX inhibitory derivatives for cancer treatment

Non-steroidal anti-inflammatory drugs (NSAIDs) such as sulindac can exert immunopotentiating effect by inhibiting the activities of cyclooxygenases (COX). However, long-term inhibition of COX can cause severe toxicities in some vital organs. This project will develop novel non-COXinhibitory sulindac derivatives and employ them as immunomodulators to augment the efficacy of cancer immunotherapies by targeting specific phosphodiesterase (PDE) instead of COX.