Immune Cell Profile Changes and Prognosis of Breast Cancer
Introduction Tumor microenvironment immunity is associated with breast cancer outcome. A high lymphocytic infiltration has been associated with response to neoadjuvant chemotherapy, but the contribution to response and prognosis of immune cell subpopulations profiles in both pre-treated and post-treatment residual tumor is still unclear.
Methods We analyzed pre- and post-treatment tumor-infiltrating immune cells (CD3, CD4, CD8, CD20, CD68, Foxp3) by immunohistochemistry in a series of 121 breast cancer patients homogeneously treated with neoadjuvant chemotherapy. Immune cell profiles were analyzed and correlated with response and survival.
Results We identified three tumor-infiltrating immune cell profiles, which were able to predict pathological complete response (pCR) to neoadjuvant chemotherapy (cluster B: 58%, versus clusters A and C: 7%). A higher infiltration by CD4 lymphocytes was the main factor explaining the occurrence of pCR, and this association was validated in six public genomic datasets. A higher chemotherapy effect on lymphocytic infiltration, including an inversion of CD4/CD8 ratio, was associated with pCR and with better prognosis. Analysis of the immune infiltrate in post-chemotherapy residual tumor identified a profile (cluster Y), mainly characterized by high CD3 and CD68 infiltration, with a worse disease free survival.
Conclusions Breast cancer immune cell subpopulation profiles, determined by immunohistochemistry-based computerized analysis, identify groups of patients characterized by high response (in the pre-treatment setting) and poor prognosis (in the post-treatment setting). Further understanding of the mechanisms underlying the distribution of immune cells and their changes after chemotherapy may contribute to the development of new immune-targeted therapies for breast cancer.
Neoadjuvant chemotherapy (NCT) is an increasingly used therapeutic strategy for early breast cancer. Besides its ability to induce clinical responses that allow breast-preserving surgery, the neoadjuvant setting is a formidable research tool to unveil mechanisms of resistance to treatment. Pathological complete response (pCR) to NCT is currently acknowledged as a surrogate endpoint for therapeutic benefit, especially in human epidermal growth factor receptor 2 (HER2) and basal breast cancer. Schedules that include sequential anthracyclines and taxanes render a higher rate of pCR, thus being the preferred neoadjuvant regimens.
Adaptive and innate immune responses play an important role in tumor immunosurveillance, and they may limit the development and growth of neoplasms. The role of immune response in breast cancer is not fully understood, but some recent observations suggest the involvement of tumor microenvironment immune balance in breast cancer response and prognosis. In particular, chemotherapy may trigger an immune response, which contributes to treatment response. Since tumor infiltrating lymphocytes (TILs) are the main actors in the response against cancer cells, they might constitute surrogate markers of the immune balance between the host and the tumor. In breast cancer, the results of studies addressing the issue of tumor immune cell infiltration have consistently demonstrated that a high lymphocytic infiltration predicts a better prognosis and a better response to NCT chemotherapy, although this benefit might be restricted to some tumor subtypes. Similarly, the relationship between some subtypes of TIL and breast cancer survival is supported by some studies. However, conflicting results exist regarding the exact prognostic or predictive value of immune cell infiltrates, and the methodological approaches are frequently different among the diverse studies.
In the setting of NCT for breast cancer, mixed results for the diverse TIL subpopulations, such as CD8 or Foxp3, have been found in different studies. Regarding the pre-treatment TIL profile, most studies have evaluated either lymphocytic infiltration as a whole or a limited set of TIL subpopulations as predictors of pCR. However, no clinical series in the neoadjuvant setting have included both a broader spectrum of TIL subpopulations and macrophage markers. The changes induced by chemotherapy on TIL populations and the immune profile of the residual tumor, that is, the chemotherapy-resistant tumor, are even less well understood, although they might be more relevant for determining prognosis. Some reports show an increase in TIL (especially CD8) in responding patients, and other data point to a decrease of some TIL subpopulations, such as Foxp3, but again no comprehensive evaluations of NCT-induced changes on immune subpopulations are available. Finally, the prognostic impact of the lymphocytic profile change has not been formally evaluated, and the only publication addressing the relevance of post-NCT lymphocytic infiltration in the residual tumor is confined to triple negative breast cancer and does not include data regarding the different lymphocyte sets.
The aim of this study was to integrate the predictive and prognostic information obtained from the multiple immune cell populations of breast cancer (CD4, CD8, Foxp3, CD20, CD68), both in the pre-treatment and post-chemotherapy residual tumor setting, and to determine the changes induced by anthracycline and taxane NCT on TIL subpopulations. We here demonstrate that pre- and post-treatment tumor-infiltrating immune cell profiles are able to identify subgroups of patients with different sensitivity to chemotherapy and with different prognosis. CD4 infiltration is identified as the main factor driving these effects. Additionally, chemotherapy-induced changes of immune infiltrates are characterized and their prognostic relevance is shown.
Abstract and Introduction
Abstract
Introduction Tumor microenvironment immunity is associated with breast cancer outcome. A high lymphocytic infiltration has been associated with response to neoadjuvant chemotherapy, but the contribution to response and prognosis of immune cell subpopulations profiles in both pre-treated and post-treatment residual tumor is still unclear.
Methods We analyzed pre- and post-treatment tumor-infiltrating immune cells (CD3, CD4, CD8, CD20, CD68, Foxp3) by immunohistochemistry in a series of 121 breast cancer patients homogeneously treated with neoadjuvant chemotherapy. Immune cell profiles were analyzed and correlated with response and survival.
Results We identified three tumor-infiltrating immune cell profiles, which were able to predict pathological complete response (pCR) to neoadjuvant chemotherapy (cluster B: 58%, versus clusters A and C: 7%). A higher infiltration by CD4 lymphocytes was the main factor explaining the occurrence of pCR, and this association was validated in six public genomic datasets. A higher chemotherapy effect on lymphocytic infiltration, including an inversion of CD4/CD8 ratio, was associated with pCR and with better prognosis. Analysis of the immune infiltrate in post-chemotherapy residual tumor identified a profile (cluster Y), mainly characterized by high CD3 and CD68 infiltration, with a worse disease free survival.
Conclusions Breast cancer immune cell subpopulation profiles, determined by immunohistochemistry-based computerized analysis, identify groups of patients characterized by high response (in the pre-treatment setting) and poor prognosis (in the post-treatment setting). Further understanding of the mechanisms underlying the distribution of immune cells and their changes after chemotherapy may contribute to the development of new immune-targeted therapies for breast cancer.
Introduction
Neoadjuvant chemotherapy (NCT) is an increasingly used therapeutic strategy for early breast cancer. Besides its ability to induce clinical responses that allow breast-preserving surgery, the neoadjuvant setting is a formidable research tool to unveil mechanisms of resistance to treatment. Pathological complete response (pCR) to NCT is currently acknowledged as a surrogate endpoint for therapeutic benefit, especially in human epidermal growth factor receptor 2 (HER2) and basal breast cancer. Schedules that include sequential anthracyclines and taxanes render a higher rate of pCR, thus being the preferred neoadjuvant regimens.
Adaptive and innate immune responses play an important role in tumor immunosurveillance, and they may limit the development and growth of neoplasms. The role of immune response in breast cancer is not fully understood, but some recent observations suggest the involvement of tumor microenvironment immune balance in breast cancer response and prognosis. In particular, chemotherapy may trigger an immune response, which contributes to treatment response. Since tumor infiltrating lymphocytes (TILs) are the main actors in the response against cancer cells, they might constitute surrogate markers of the immune balance between the host and the tumor. In breast cancer, the results of studies addressing the issue of tumor immune cell infiltration have consistently demonstrated that a high lymphocytic infiltration predicts a better prognosis and a better response to NCT chemotherapy, although this benefit might be restricted to some tumor subtypes. Similarly, the relationship between some subtypes of TIL and breast cancer survival is supported by some studies. However, conflicting results exist regarding the exact prognostic or predictive value of immune cell infiltrates, and the methodological approaches are frequently different among the diverse studies.
In the setting of NCT for breast cancer, mixed results for the diverse TIL subpopulations, such as CD8 or Foxp3, have been found in different studies. Regarding the pre-treatment TIL profile, most studies have evaluated either lymphocytic infiltration as a whole or a limited set of TIL subpopulations as predictors of pCR. However, no clinical series in the neoadjuvant setting have included both a broader spectrum of TIL subpopulations and macrophage markers. The changes induced by chemotherapy on TIL populations and the immune profile of the residual tumor, that is, the chemotherapy-resistant tumor, are even less well understood, although they might be more relevant for determining prognosis. Some reports show an increase in TIL (especially CD8) in responding patients, and other data point to a decrease of some TIL subpopulations, such as Foxp3, but again no comprehensive evaluations of NCT-induced changes on immune subpopulations are available. Finally, the prognostic impact of the lymphocytic profile change has not been formally evaluated, and the only publication addressing the relevance of post-NCT lymphocytic infiltration in the residual tumor is confined to triple negative breast cancer and does not include data regarding the different lymphocyte sets.
The aim of this study was to integrate the predictive and prognostic information obtained from the multiple immune cell populations of breast cancer (CD4, CD8, Foxp3, CD20, CD68), both in the pre-treatment and post-chemotherapy residual tumor setting, and to determine the changes induced by anthracycline and taxane NCT on TIL subpopulations. We here demonstrate that pre- and post-treatment tumor-infiltrating immune cell profiles are able to identify subgroups of patients with different sensitivity to chemotherapy and with different prognosis. CD4 infiltration is identified as the main factor driving these effects. Additionally, chemotherapy-induced changes of immune infiltrates are characterized and their prognostic relevance is shown.
SHARE
![Pediatric Supportive Care (PDQ®): Supportive care - Patient Information [NCI]-Overview](https://cdnus.oss-us-west-1.aliyuncs.com/libs/images/NewsJpg/cate_6/072_215x160.jpg)
