scholarly journals Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yeon Hee Park ◽  
Samir Lal ◽  
Jeong Eon Lee ◽  
Yoon-La Choi ◽  
Ji Wen ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Pathologic Complete Response ◽  
Tumor Infiltrating Lymphocytes ◽  
Transcriptome Profiling ◽  
Complete Response ◽  
Strongly Correlated ◽  
Breast Cancers ◽  
Breast Cancer Cohort ◽  
Tumor Biopsies ◽  
Infiltrating Lymphocytes

AbstractTo elucidate the effects of neoadjuvant chemotherapy (NAC), we conduct whole transcriptome profiling coupled with histopathology analyses of a longitudinal breast cancer cohort of 146 patients including 110 pairs of serial tumor biopsies collected before treatment, after the first cycle of treatment and at the time of surgery. Here, we show that cytotoxic chemotherapies induce dynamic changes in the tumor immune microenvironment that vary by subtype and pathologic response. Just one cycle of treatment induces an immune stimulatory microenvironment harboring more tumor infiltrating lymphocytes (TILs) and up-regulation of inflammatory signatures predictive of response to anti-PD1 therapies while residual tumors are immune suppressed at end-of-treatment compared to the baseline. Increases in TILs and CD8+ T cell proportions in response to NAC are independently associated with pathologic complete response. Further, on-treatment immune response is more predictive of treatment outcome than immune features in paired baseline samples although these are strongly correlated.

scholarly journals Clinical Significance of Expression of Immunoadjuvant Molecules (LAG-3, TIM-3, OX-40) in Neoadjuvant Chemotherapy for Breast Cancer

2021 ◽  
Author(s):  
Yuka Asano ◽  
Shinichiro Kashiwagi ◽  
Sae Ishihara ◽  
Koji Takada ◽  
Wataru Goto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Cell Activity ◽  
Growth Factor Receptor ◽  
Tumor Infiltrating Lymphocytes ◽  
Complete Response ◽  
Breast Cancers ◽  
Malignant Breast ◽  
Immune Response To Cancer ◽  
Infiltrating Lymphocytes

Abstract Purpose Various immunosuppressive factors that inhibit the immune response to cancer are present in cancer cells and the cancer microenvironment. Co-inhibitory and co-stimulatory receptors are dynamically expressed on T-cells as immunoadjuvant molecules that regulate the state of T-cell activity. In this report we focus on immunoadjuvant molecules such as LAG-3, TIM-3, and OX-40, for which there have been few published reports. We investigated the expression of LAG-3, TIM-3, and OX-40 in tumor-infiltrating lymphocytes (TILs), and clinically verified the significance of that expression in relation to neoadjuvant thermotherapy (NAC). Methods A total of 177 patients with resectable early-stage breast cancer were treated with NAC. Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki67, LAG-3, TIM-3 and OX-40 status were assessed by immunohistochemistry. Results There were 47 (26.6%) patients with high LAG-3 expression, 31 (17.5%) patients had high TIM-3 expression, and 32 (18.1%) patients had high OX-40 expression. The group with low-LAG-3 expression was significantly smaller than the group with high expression in triple-negative breast cancer (TNBC) (p = 0.038) and HER2-enriched breast cancer (HER2BC) (p = 0.021), and the total number of pathological complete response (pCR) patients was greater (p < 0.001). In TNBC and HER2BC, the pCR rate was significantly higher in the low-LAG-3 expression group than in the high-LAG-3 expression group (p < 0.001) (p = 0.020). Moreover, on multivariate analysis also showed that low-LAG-3 expression status was an independent factor to predict the favorable prognosis (p = 0.014, HR = 8.124) (p = 0.048, HR = 10.400). Conclusions Our findings suggest that LAG-3 may become a biomarker in highly malignant breast cancers such as TNBC and HER2BC that can predict the therapeutic efficacy of NAC.

Predictive value of tumor infiltrating lymphocytes (TIL) for response to breast cancer neoadjuvant chemotherapy (NCT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 585-585
Author(s):  
Elena Garcia-Martinez ◽  
Gines Luengo-Gil ◽  
Asuncion Chaves ◽  
Lorena Velazquez ◽  
Enrique Gonzalez-Billalabeitia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Predictive Value ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Residual Tumor ◽  
Complete Response ◽  
Before And After ◽  
Pre Treatment ◽  
Infiltrating Lymphocytes

585 Background: The association of tumor microenvironment immune response with outcome after breast cancer (BC) NCT has been suggested by several studies. However, the relevance of each TIL subpopulation is still controversial. The objective of this study was to evaluate the predictive and prognostic value of TIL before and after NCT in patients with BC. Methods: We analyzed TIL and CD68 cells in pre- and post-chemotherapy biopsies of BC patients treated with NCT (80.4% sequential AC-docetaxel). A tissue microarray with paired pre- and post-NCT biopsies was built, and stained with immunohistochemistry (IHC) for CD3, CD4, CD8, CD20, FOXP3 and CD68. Morphometric analysis (TIL count/mm2) was performed after slide scanning and digitalization. Results: We included 121 consecutive patients with invasive BC, most of them with stages IIB (28%) or IIIA-C (56.4%). IHC phenotype: 50.4% Her2- hormone-sensitive (HS), 13.2% Her2+ HS, 10.7% Her2+ non-HS, and 21.5% triple negative. Pathologic complete response (pCR): 17.4%. Median overall survival (OS) and disease free survival (DFS) has not been reached (median follow-up: 60 months). Higher than median pre-NCT TIL infiltration was predictive of pCR to NCT: CD3 > 172/mm2 (p=0.001; Hazard Ratio [HR]: 9,61, 95% confidence interval [95%CI] 2.49–37.02); CD4 > 67/mm2 (p=0.001; HR: 8.82, 95%CI 2.43–31.96); CD20 > 42/mm2 (p=0.001; HR: 8.71, 95%CI 2.31–32.74). Logistic regression multivariate models including grade and IHC phenotype confirmed the independent predictive value of higher pre-NCT CD3, CD4, and CD20 for pCR. In the group of patients with HS Her2- BC without pCR (n=44), higher infiltration (cut-point: median value) by some TIL subpopulations and by CD68 cells in post-NCT residual tumor associated to lower DFS: CD8 > 37/mm2 (log-rank; p=0.04), CD20 > 14/mm2 (p=0.07) and CD68> 39/mm2 (p=0.06). Conclusions: Higher pre-treatment CD3, CD4 and CD20 TIL predicted pRC in patients with invasive BC receiving anthracyclines and taxanes NCT, while higher infiltration of residual tumor by CD8 associated to worse DFS in patients with HS Her2- BC without pCR after NCT. TIL might be useful as predictive factors in the setting of NCT for BC [Supported by GEICAM-Beca Ana Balil].

scholarly journals Immune microenvironment changes induced by neoadjuvant chemotherapy in triple-negative breast cancers: the MIMOSA-1 study

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Victor Sarradin ◽  
Amélie Lusque ◽  
Thomas Filleron ◽  
Florence Dalenc ◽  
Camille Franchet
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Triple Negative ◽  
Tumor Infiltrating Lymphocytes ◽  
Complete Response ◽  
Breast Cancers ◽  
Immune Microenvironment ◽  
Prognostic Information ◽  
Immune Biomarkers ◽  
Significant Difference ◽  
Infiltrating Lymphocytes

Abstract Background The immune microenvironment (IME) of triple-negative breast cancers (TNBCs) and its modulation by neoadjuvant chemotherapy (NACT) remain to be fully characterized. Our current study aims to evaluate NACT-induced IME changes and assess the prognostic value of specific immune biomarkers. Methods Tumor-infiltrating lymphocytes (TILs) were identified from hematoxylin-eosin-stained sections of paired pre- and post-NACT tumor samples from a TNBC cohort (n = 66) and expression of PD-L1, TIM-3, and LAG-3 evaluated by immunohistochemistry. Results Overall TIL counts and PD-L1 expression did not differ pre- and post-NACT, but there was a response-specific statistically significant difference. TIL counts decreased in 65.5% of patients who achieved a pathological complete response (pCR) and increased in 56.8% of no-pCR patients (p = 0.0092). PD-L1 expression was significantly more frequently lost after NACT in pCR than in no-pCR patients (41.4% vs 16.2%, p = 0.0020). TIM-3 positivity (≥ 1%) was significantly more frequent after NACT (p < 0.0001) with increases in expression levels occurring more frequently in no-pCR than in pCR patients (51.4% vs 31%). LAG-3 expression significantly decreased after NACT, but there was no difference between response groups. Before NACT, a high TIL count (> 10%) was significantly associated with better overall survival (OS), p = 0.0112. After NACT, PD-L1 positivity and strong TIM-3 positivity (≥ 5%) were both associated with significantly worse OS (p = 0.0055 and p = 0.0274, respectively). Patients positive for both PD-L1 and TIM-3 had the worst prognosis (p = 0.0020), even when only considering patients who failed to achieve a pCR, p = 0.0479. Conclusions NACT induces significant IME changes in TNBCs. PD-L1 and TIM-3 expression post-NACT may yield important prognostic information for TNBC patients.

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