The Zhou Lab

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 “gatekeeper” 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.