Potential Therapeutic Relevance For TIM-3 In Breast Cancer Patients

Since the first FDA approval of an immune checkpoint blockade (ICB) therapy in 2011, immunotherapy has increasingly become a standard-of-care treatment for cancer. ICB can work exceedingly well in a subset of patients, but disparities in response rates exist, particularly between tumor types (1).

The other major factor predicting response to ICB is the extent to which a patient has a preexisting immune response against the tumor. Thus, patients with high numbers of cytotoxic T cells, the primary cell type responsible for attacking tumors, are more likely to display durable responses to ICB (2).

This has led to intense interest in identifying mechanisms that will expand upon the range of patients who respond to ICB. One area of interest has been on targeting the cell type responsible for initiating the cytotoxic T cell response, known as dendritic cells (DCs). DCs have long been of interest in cancer research for their potential role in vaccination, but the best way to target these cells to improve immune responses against tumors remains unknown (3).

In a paper published in the January 2018 issue of Cancer Cell, de Mingo Pulido et al. examined DCs for potential therapeutic targets of interest and identified expression of the molecule TIM-3 (4). TIM-3 is an immune checkpoint molecule — often found on T cells — that is currently being evaluated as a target in ICB trials. In contrast to previous publications, however, the authors found that TIM-3 is expressed primarily by DCs in both human breast cancer and mouse models of breast cancer. To determine the therapeutic potential of this expression, an anti-TIM-3 antibody was evaluated alone or in combination with paclitaxel, a standard-of-care chemotherapy for breast cancer. Treatment with the combination significantly reduced the rate of tumor growth in mice, as compared to treatment with paclitaxel alone. This result points to the potential for integrating immune-regulatory therapies into standard-of care-chemotherapy. Indeed, a number of clinical trials are currently examining the efficacy of combining chemotherapy with ICB, with positive results already reported for anti-PD-1 in lung cancer (5).

The authors next sought to confirm that DCs were the functional target of the anti-TIM-3 antibody using mouse models that lacked DCs, either as a result of genetic engineering or due to cell-type specific depletion. Consistent with expectations, both approaches to remove DCs abrogated response to the combination therapy. The authors further showed that in response to anti-TIM-3 and paclitaxel, DCs upregulated production of certain molecules — known as chemokines — that are known to be critical for recruiting T cells into tumors. When the function of these chemokines was blocked, the effects of anti-TIM-3 were also blocked, indicating that increased chemokine production by DCs was responsible for the efficacy of anti-TIM-3 therapy.

These data also suggested that T cells would be needed for the efficacy of anti-TIM-3 therapy, despite the fact that T cells in the tumor did not express high levels of TIM-3. Although the absolute number of T cells in the tumors did not change, the T cells in anti-TIM-3 treated tumors showed higher expression of cytotoxic and inflammatory molecules, indicating an improved T cell response.  Consistent with this observation, depleting T cells also prevented the tumors from responding to combination therapy. This indirect promotion of a T cell response against tumors by anti-TIM-3 has implications for the patient populations that may benefit from this therapy. Currently, administration of ICB frequently involves checking to see whether the target of interest is expressed by the tumor.  The indirect enhancement of T cell function by anti-TIM-3 therapy suggests that patients that lack TIM-3⁺ T cells may still benefit from therapy and that this group should potentially be included in clinical trials designed to test the efficacy of anti-TIM-3.

Overall, the paper by de Mingo Pulido et al. highlights the importance of considering targets beyond those expressed by T cells when designing immunotherapies. This includes promoting the function of DCs, as shown in this paper, as well as ablating suppressive cells within tumors that can interfere with cytotoxic T cell function. Because breast cancer is not generally considered an immunogenic tumor type, the study also hints that promoting DC activity could boost the immune response in patients that would not normally be expected to respond to ICB. That said, it remains to be determined if TIM-3 therapies will be useful in the clinic, and what the best therapeutic combinations will be.

These findings are described in the article entitled TIM-3 Regulates CD103⁺ Dendritic Cell Function and Response to Chemotherapy in Breast Cancer, recently published in the journal Cancer Cell. This work was conducted by Álvaro de Mingo Pulido, Alycia Gardner, Shandi Hiebler, Hatem Soliman, and Brian Ruffell from the H. Lee Moffitt Cancer Center and Research Institute, Hope S. Rugo and Matthew F. Krummel from the University of California San Francisco, and Lisa M. Coussens at Oregon Health and Science University.

References:

1. Yarchoan, M., Hopkins, A., and Jaffee, E.M. (2017). Tumor mutational burden and response rate to PD-1 inhibition. New England Journal of Medicine 377, 2500-2501.
2. Gnjatic, S., Bronte, V., Brunet, L.R., Butler, M.O., Disis, M.L., Galon, J., Hakansson, L.G., Hanks, B.A., Karanikas, V., and Khleif, S.N. (2017). Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy. Journal for immunotherapy of cancer 5, 44.\
3. Gardner, A., and Ruffell, B. (2016). Dendritic cells and cancer immunity. Trends in immunology 37, 855-865.
4. de Mingo Pulido, Á., Gardner, A., Hiebler, S., Soliman, H., Rugo, H.S., Krummel, M.F., Coussens, L.M., and Ruffell, B. (2018). TIM-3 Regulates CD103+ Dendritic Cell Function and Response to Chemotherapy in Breast Cancer. Cancer cell 33, 60-74. e66.
5. Rizvi, N.A., Hellmann, M.D., Brahmer, J.R., Juergens, R.A., Borghaei, H., Gettinger, S., Chow, L.Q., Gerber, D.E., Laurie, S.A., and Goldman, J.W. (2016). Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 34, 2969-2979.