Three Key factors for breast cancer to respond to immunotherapy!
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Three Key factors for breast cancer to respond to immunotherapy!
The emergence of immunotherapy has greatly changed the treatment of solid tumor cancers, including triple-negative breast cancer (TNBC), which is known as the most vicious breast cancer.
However, from the results of clinical trials, PD-1/PD-L1 inhibitors only work for some TNBC patients, and we are not fully clear about what characteristics these patients have.
On Sep 06, a team from the University of Cambridge and a team from the San Raffaele Hospital in Italy jointly published a paper on Nature, analyzing the impact of TNBC’s multicellular spatial distribution on immunotherapy efficacy.
The study results suggest that cell phenotype, activation state and spatial distribution are the key three factors that affect immunotherapy efficacy, and they are significantly different in immunotherapy-sensitive tumors and resistant tumors.
The study also pointed out that the proportion of proliferative CD8+TCF1+T cells and MHC I＆IIhi cancer cells is the main predictor of immunotherapy, followed by the interaction between cancer cells and B cells and granzyme B+T cells.
The effect of immunotherapy is affected by many factors, and the characteristics of the tumor microenvironment (TME) are also very important.
Understanding the cellular composition and multicellular spatial distribution of the tumor microenvironment can greatly facilitate the exploration of immunotherapy applicability conditions.
The samples analyzed in the study came from a clinical trial NeoTRIP, which was a 1:1 randomized controlled trial of neoadjuvant chemotherapy (carboplatin + albumin-bound paclitaxel) and chemotherapy + immunotherapy (carboplatin + albumin-bound paclitaxel + anti-PD-L1 antibody atezolizumab). The study sampled at three time points before, during, and after treatment, and used imaging mass cytometry (IMC) to analyze the expression of 43 proteins at subcellular resolution in FFPE tumor tissue samples to accurately characterize TME and key cancer cell phenotypes. A total of 1855 high-quality tissue images were obtained.
Experimental flow and combination of marker proteins for characterizing cells
Since immunotherapy can induce T cell proliferation, researchers believe that the type of proliferating cells before treatment will affect immunotherapy efficacy. The researchers analyzed the proportion of proliferating cells in different cell phenotypes and found that proliferating MHC I＆IIhi cancer cells were the best predictors of immunotherapy response.
Cell phenotypes significantly associated with immunotherapy efficacy
The samples during treatment were taken on the first day of the second treatment cycle. The researchers analyzed the relationship between cell density, cell-cell interactions and immunotherapy response in the samples. Interestingly, the predictors of immunotherapy during treatment were not the same as before treatment. The characteristic of responding to immunotherapy was CD8+GZMB+T cell accumulation, while anaplastic CD79a+ plasma cells and CD15+ cancer cell interactions represented tumor resistance.
Throughout the changes in cells during immunotherapy, it can be seen that immune cells increase sharply during treatment and decrease after treatment, accompanied by a decrease in cancer cells and an increase in matrix cells. In patients who responded to immunotherapy, the increase in T cells and antigen-presenting cells was very obvious.
Changes in different cell phenotypes
In order to find effective predictors of immunotherapy, researchers performed multivariate logistic regression model analysis. The results showed that TME activation and tumor structure played an important role in treatment response, which means that biopsy in early treatment can help predict prognosis and guide treatment decisions.
Before starting treatment, among all 14 contributing predictors, proliferative CD8+TCF1+T cells were the best predictors, followed by proliferative MHC I＆IIhi cancer cells, cancer cell-B cell interactions, cancer cell-CD8+GZMB+T cell interactions.
In summary, the results of this study indicate that cell phenotype, activation state and spatial organization jointly determine TNBC immunotherapy efficacy. Systematic analysis of them is the basis for precision therapy. This also means that biopsy is necessary in early treatment, which can help identify TNBC patients who are suitable for immunotherapy.
References:
[1]doi.org/10.1038/s41586-023-06498-3
Three Key factors for breast cancer to respond to immunotherapy!
(source:internet, reference only)
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