CD8+ T cells play a large role in identifying and eliminating malignant cells. T cells naturally express T cell receptors (TCRs) which allow them to recognize infected or cancerous cells. However, tumor microenvironments often suppress T cells and can ultimately cause T cells to become dysfunctional or depleted. One tumor type that creates a particularly immunosuppressive microenvironment is pancreatic ductal adenocarcinoma (PDA), the most common pancreas cancer. PDA is very difficult to treat, as it creates a barrier of fibrous tissue around the tumor, making it resistant to chemotherapy, radiotherapy, and immune checkpoint blockade. In some cases, the tumor can be surgically removed, although it is most often diagnosed after it has metastasized and surgery is no longer effective. In addition, PDA is very aggressive with a five-year survival rate of 9%. Because of these difficulties in treating PDA, the laboratories of Drs. Philip Greenberg and Sunil Hingorani tested a therapy using T cells engineered to express a TCR with high affinity for mesothelin, an antigen highly expressed in PDA. The work they published together in 2015 showed that although the mesothelin-specific T cells (TCRMsln) efficiently targeted tumor cells and prolonged survival in a preclinical mouse model developing autochtonous PDA in vivo, they became more dysfunctional as more time passed after transfer.
The two labs have continued the collaboration and recently published another study featuring the engineered T cell therapy in Cancer Immunology Research. This time, the authors sought to prevent T cell dysfunction through modulating or depleting tumor associate macrophages (TAMs), key players in immunosuppression and inhibition of T cells in the tumor microenvironment. As TAMs require CSF1 to survive, the authors injected an antibody to block its receptor, anti-Csf1R. Blocking with anti-Csf1R reduced the number of patrolling monocytes and inflammatory monocytes, two types of TAMs, in circulation and in the tumor. Anti-Csf1R administration also decreased the amount of fibrous tissue surrounding the tumor. Furthermore, blocking Csf1R led to increased numbers of infiltrating endogenous CD8+ T cells. However, despite the depletion of immunosuppressive TAMs, anti-Csf1R did not prevent the dysfunction of TCRMsln cells, as evidenced by their increased expression of the inhibitory receptor PD-1 and their lowered ability to secrete IFN-g ex vivo in response to restimulation with mesothelin.
The authors next studied how re-education of TAMs affects TCRMsln cells. They administered agonistic anti-CD40, which stimulates entry of monocytes into PDA which can differentiate into macrophages with anti-tumor properties or into dendritic cells. The authors found that anti-CD40 treatment resulted in an increased expansion and persistence of TCRMsln cells. In addition, the TCRMsln cells expressed lower levels of PD-1, but anti-CD40 treatment did not rescue their ability to secrete IFN-g. Moreover, the treatment increased apoptosis of tumor cells and decreased the amount of fibrous tissue around the tumor. Anti-CD40 administration also increased the number of inflammatory monocytes while having no significant effect on the number of patrolling monocytes in the tumor. Rather, anti-CD40 treatment reduced the frequency of those patrolling monocytes which expressed PD-1, suggesting that anti-CD40 decreases the immunosuppressive activity of these TAMs.
The authors showed that while TCRMsln cells are able to eliminate pancreas cancer cells in vivo, TAMs must be modulated in order to maintain the effector function of and sufficient numbers of TCRMsln cells to eradicate the tumor. Although modulating TAMs with anti-CD40 showed significant improvements in longevity of TCRMsln cells, they eventually became less effective. Future studies could test more ways of modulating immune cells in the tumor microenvironment in a way that they are more capable of promoting the maintenance of TCRMsln cell function.
This work was supported by AACR Pancreatic Cancer Action Network, the American Cancer Society, the National Cancer Institute, Giles W. and Elise G. Mead Foundation, Pancreatic Cancer Action Network, and Juno Therapeutics.
Fred Hutch/UW Cancer Consortium members Robert Pierce, Philip Greenberg, and Sunil Hingorani contributed to this research.
Stromnes IM, Burrack AL, Hulbert A, Bonson P, Black C, Brockenbrough JS, Raynor JF, Spartz EJ, Pierce RH, Greenberg PD, Hingorani SR. Differential Effects of Depleting versus Programming Tumor-Associated Macrophages on Engineered T Cells in Pancreatic Ductal Adenocarcinoma. Cancer Immunol Res. 2019 Apr 26;. doi: 10.1158/2326-6066.CIR-18-0448. [Epub ahead of print]