Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy

Abstract

Cancer immunotherapy has altered the management of human malignancies, improving outcomes in an expanding list of diseases. Breast cancer - presumably due to its perceived low immunogenicity - is a late addition to this list. Furthermore, most of the focus has been on the triple negative subtype because of its higher tumor mutational load and lymphocyte-enriched stroma, although emerging data show promise on the other breast cancer subtypes as well. To this point the clinical use of immunotherapy is limited to the inhibition of two immune checkpoints, Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4). Consistent with the complexity of the regulation of the tumor – host interactions and their lack of reliance on a single regulatory pathway, combinatory approaches have shown improved efficacy albeit at the cost of increased toxicity. Beyond those two checkpoints though, a large number of co-stimulatory or co-inhibitory molecules play major roles on tumor evasion from immunosurveillance. These molecules likely represent future targets of immunotherapy provided that the promise shown in early data is translated into improved patient survival in randomized trials. The biological role, prognostic and predictive implications regarding breast cancer and early clinical efforts on exploiting these immune-related therapeutic targets are herein reviewed.

Targeting the TIGIT-PVR immune checkpoint axis as novel therapeutic option in breast cancer

“…[37][38][39] These observations could indicate that different immune checkpoint axes other than PD-1 or CTLA-4 may be more relevant and therefore better targets in breast cancer. 40 Our present study provides strong evidence that the PVR-TIGIT axis may represent a promising therapeutic target for breast cancer patients.…”

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

“…Unlike immunologically "hot" tumors such as lung cancer, melanoma, and bladder cancer, most breast carcinomas are not inherently immunogenic. Consequently, they typically exhibit low T-cell infiltration and are unlikely to benefit from immune checkpointcentric therapies [1][2][3][4][5]. Exceptions to this immunologically "cold" rule of breast carcinomas are the socalled basal-like [6][7][8][9][10][11][12][13][14] and HER2-positive [15][16][17][18][19][20] subtypes, both of which show evidence of immunogenicity including tumor immune infiltrates and stromal and intratumoral tumor-infiltrating lymphocytes, a good predictive marker for responses to immunotherapy.…”

Enhancing Triple Negative Breast Cancer Immunotherapy by ICG‐Templated Self‐Assembly of Paclitaxel Nanoparticles

“…[7][8][9] Despite promising, the TNBC patients rarely benefit from current ICB therapy due to low immunogenicity and immunosuppressive tumor micro environment (ITM) of TNBC tumors. [10][11][12][13][14][15][16] Thus, complementary approaches to enhance the immunogenicity and reverse the ITM remain a formidable challenge for improving immunotherapy of TNBC. [17][18][19][20] The combination of ICB therapy with chemotherapy, photodynamic therapy (PDT) or radiotherapy has displayed synergistic antitumor effect to facilitate intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and overcome the ITM.…”