Tumor-Infiltrating Lymphocytes in Breast and Female Genital Tract Cancers: Overlooked Potential and Unexplored Frontiers

Abstract

Background: The growing success of cancer immunotherapies has led to significant advances in oncology. However, despite these promising developments, cancer-related mortality remains high for common cancer types such as breast and lower female genital tract cancers.

Method: Here, we synthesize recent findings on the prognostic relevance of tumor-infiltrating lymphocytes (TILs) in breast, endometrial, tubo-ovarian, and vulvar cancer. Our analysis covers the relationship between TIL counts and density, immune cell subtype combinations, immunotherapy approaches, and patient outcomes.

Results: High TIL infiltration, especially CD8⁺ T-cells, generally correlates with improved outcomes such as in endometrial cancer (especially the POLE-ultramutated subgroup), invasive breast cancer, and ovarian epithelial tumors. However, in ductal carcinoma in situ (DCIS) of the breast, elevated TIL counts are linked to a worse prognosis. Ethnicity, the tumor microenvironment (TME), and molecular profiles further complicate the prognostic utility of TILs.

Conclusions: TIL-based therapies have shown potential in personalized immunotherapy, particularly in recurrent, refractory ovarian cancer. Limited research on rarer gynecologic tumors hinders broader clinical applications.

Keywords: breast cancer; endometrial cancer; fallopian tube; immunotherapy; ovarian cancer; review; tumor microenvironment (TME); tumor‐infiltrating lymphocytes (TILs); vulvar cancer.

FIGURE 1

Multi‐step mechanism of tumor‐infiltrating lymphocytes (TILs). (A) Migration: TILs migrate via the bloodstream to reach tumor sites, guided by cytokines (blue dots) and adhesion molecules (green). (B) Tumor recognition: On site, TILs invade the collagen matrix (light blue) of the tumor microenvironment (TME) and are confronted with a more or less hostile local cell infiltrate, e.g., cells of the innate immunity such as (tumor‐associated) macrophages (TAMs), tumor‐infiltrating neutrophils (TINs), and dendritic cells. TAMs can be polarized into an M1‐ (green) and M2‐subgroup (purple). While M1‐macrophages secrete pro‐inflammatory cytokines (red and purple dots), e.g., Tumor necrosis factor (TNF)‐α, M2‐macrophages mediate anti‐inflammatory action (light blue dots). (C) Effect: TILs recognize and interact with tumor‐associated antigens (blue triangle), leading to a release of cytotoxic granules (pink dots). Created in BioRender.com.

FIGURE 2

Breast cancer. (A) Moderately differentiated invasive breast cancer (non‐special type, BRE* (Bloom‐Richardson‐Elston)‐Score 3/2/1, Grade 2), hormone receptor (HR) positive (HR+) with no amplification of HER2 gene, showing very few tumor infiltrating lymphocytes (TILs). (B) Poorly differentiated invasive breast cancer (non‐special type, BRE‐Score 3/3/3, Grade 3), hormone receptor (HR) positive (HR+) with amplification of HER2 gen, showing numerous peri‐ and intratumoral TILs. (C) CD3⁺ stain showing numerous T‐lymphocytes. (D) CD20⁺ showing some B‐lymphocytes. (E) FOXP3 showing sparse CD4⁺ T‐regulatory cell (T_reg) infiltration—red arrows. (F) PD‐L1 immunohistochemical stain (VENTANA PD‐L1 (SP142)) showing focal membranous positivity in tumor and in immune cells. *The Bloom‐Richardson‐Elston (BRE)‐score quantifies the amount of gland formation/nuclear features/mitotic activity for breast cancer grading.

FIGURE 3

Vaginal, vulvar, ovarian, and endometrial cancer. (A) Squamous cell carcinoma (SCC) of the vulva, showing numerous TILs. (B) HPV‐dependent squamous cell carcinoma (SCC) of the vagina, showing numerous TILs. (C) High‐grade serous carcinoma (HGSC) with surrounding inflammatory cells. (D) Poorly differentiated endometrioid adenocarcinoma of the uterus (Grade 3), with a pathogenic mutation of the POLE gene, showing numerous tumor‐infiltrating lymphocytes (TILs).