Researchers deem tumor-infiltrating lymphocytes valid prognostic biomarker in TNBC

For decades, pathologists have noted that most human tumors are infiltrated by lymphocytes. The clinical significance of tumor-infiltrating lymphocytes (TILs) came into focus over the past decade, with large studies of sufficient size to detect statistically significant correlations with survival. The strongest evidence for tumor infiltration by T cells and favorable clinical outcome has been established in colorectal carcinoma. Similar correlations have now been observed in essentially all tumor types, including melanoma, head and neck cancer, lung cancer, and others. Over the past year, three large studies have firmly established the clinical significance of TILs in breast cancer. The largest study followed clinical outcomes of 12,439 newly diagnosed breast cancer patients in the United Kingdom and Canada over the course of 10 years. The study showed a survival benefit of CD8-positive T cells within breast tumors in both triple-negative and ER-negative/HER2-positive patients. A survival benefit from CD8-positive T cells within triple-negative breast tumors was also shown in two additional studies: ECOG and FinHER studies representing an additional 1,491 patients analyzed.

Together, these studies firmly established the prognostic significance of tumor-infiltrating CD8-positive T cells in triple-negative and HER2-positive breast cancer. Furthermore, these studies also found that tumor-infiltrating CD8-positive T cells are predictive of clinical benefit from trastuzumab and anthracyclines. Thus, the presence of intratumoral CD8-positive T cells can help guide breast cancer patient management and should be included in routine pathologic examinations – a concept the authors called "immunoscore."

However, T cells are often exhausted and dysfunctional within the tumor microenvironment. Recent studies have shown that tumor-infiltrating T cells express several immune checkpoint molecules – including CTLA-4, PD-1, TIM-3, and LAG-3 – which when engaged with their counterligands (B7 and PDL-1, for example) – leads to inhibition of T-cell function. This spawned the development of antibodies to block immune checkpoint molecules, which have demonstrated exciting clinical efficacy. An anti–CTLA-4 antibody (ipilimumab, Yervoy) demonstrated efficacy in phase III clinical trials and was approved by the U.S. Food and Drug Administration for metastatic melanoma in 2011. Antibodies blocking PD-1, or its counterligand PD-L1, are under clinical development by at least seven companies. Phase II data show encouraging clinical responses and potentially less toxicities than anti–CTLA-4. Importantly, these immune checkpoint inhibitors led to survival curves that plateau at 15%-25%, raising the exciting possibility that some patients may be cured – by agents that act on the host immune system only. These results further strengthen the notion that the host immune system can respond to cancer, that the success of the endogenous antitumor immune response determines clinical outcome and response to even conventional therapies, and that this immune response can be further enhanced for clinical benefit.

Other immune cell types also infiltrate human tumors, including B, NK, and myeloid cells. The balance of these different immune cell populations within tumors – and tumor-draining lymph nodes (TDLNs) – likely drives clinical outcome. Future studies need to account for this additional complexity, which will be possible using novel flow cytometry and image analysis approaches. A deeper understanding of the interplay between different immune cell populations within tumors and TDLNs will uncover ways to enhance the total effect of cancer immunotherapies, including checkpoint inhibitors and adoptive T-cell therapy.

Dr. Peter P. Lee is Billy Wilder Endowed Professor and Chair, department of cancer immunotherapeutics and tumor immunology at the City of Hope Comprehensive Cancer Center, Duarte, Calif. Dr. Lee said he had no relevant financial conflicts.