Chemoresistance in Breast Cancer Patients Associated With Changes in P2X7 and A2A Purinergic Receptors in CD8+ T Lymphocytes.

Victor Manuel Ruiz-Rodríguez,Nallely López-López,Diana Patricia Portales-Pérez,Sofia Bernal-Silva,Jaime Arturo Guel-Pañola,Mariana Haydee García-Hernández,José De Jesús Zermeño-Nava,Eneida Turiján-Espinoza,Esther Layseca-Espinosa,Ana María Estrada-Sánchez,Ezequiel M Fuentes-Pananá

doi:10.3389/fphar.2020.576955

Abstract

Breast cancer (BRCA) is the most frequent cancer type that afflicts women. Unfortunately, despite all the current therapeutic strategies, many patients develop chemoresistance hampering the efficacy of treatment. Hence, an early indicator of therapy efficacy might aid in the search for better treatment and patient survival. Although emerging evidence indicates a key role of the purinergic receptors P2X7 and A2A in cancer, less is known about their involvement in BRCA chemoresistance. In this sense, as the chemotherapeutic treatment stimulates immune system response, we evaluated the expression and function of P2X7 and A2A receptors in CD8+ T cells before and four months after BRCA patients received neoadjuvant chemotherapy. The results showed an increase in the levels of expression of P2X7 and a decrease in the expression of A2A in CD8+ T cells in non-chemoresistant (N-CHR) patients, compared to chemoresistant (CHR) patients. Interestingly, in CHR patients, reduced expression of P2X7 occurs along with a decrease in the CD62L shedding and the production of IFN-γ. In the case of the A2A function, the inhibition of IFN-γ production was not observed after chemotherapy in CHR patients. A possible relationship between the modulation of the expression and function of the P2X7 and A2A receptors was found, according to the molecular subtypes, where the patients that were triple-negative and human epidermal growth factor receptor 2 (HER2)-enriched presented more alterations. Comorbidities such as overweight/obesity and type 2 diabetes mellitus (T2DM) participate in the abnormalities detected. Our results demonstrate the importance of purinergic signaling in CD8+ T cells during chemoresistance, and it could be considered to implement personalized therapeutic strategies.

Highlights

Breast cancer (BRCA) is the most common type of cancer in women, both in developed and underdeveloped countries
The P2X7 receptor participates in immune cells activation response, differentiation, and production of proinflammatory cytokines, and it promotes cell death by forming a non-selective pore, mainly in cells with high expression of the receptor as monocytes/macrophages (Surprenant and North, 2009; Di Virgilio et al, 2017; Adinolfi et al, 2018)
It is of great interest to determine whether the P2X7 receptor expressed in CD8+ T lymphocytes plays a role in the chemoresistance of BRCA patients

Summary

Introduction

Breast cancer (BRCA) is the most common type of cancer in women, both in developed and underdeveloped countries. BRCA can develop in the milk ducts (ductal cancers) or the milk-producing glands (lobular cancers). Biopsy evaluation provides information about the degree of aggressiveness of the tumor and the presence or absence of specific markers that aid in making decisions about the best chemotherapy option In this sense, patients might fall into one of the four intrinsic molecular groups depending on the presence of estrogen receptor (ER), progesterone (PR) or human epidermal growth factor receptor 2 (HER2): luminal A (ER+, PR+, HER2−), luminal B (ER+, PR+/−, HER2+/−), HER2enriched (ER−, PR−, HER2+), and triple-negative (ER−, PR−, HER2−) (Breastcancer.org, 2018)

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