Discrepant CD3+ TILs in PD-L1-Negative NSCLC: Favorable Outcome in an Elderly Patient Treated With Nivolumab, Ipilimumab, and Chemotherapy.

BACKGROUND Immune-checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T lymphocyte antigen-4 (CTLA-4) have revolutionized the treatment landscape of non-small cell lung cancer (NSCLC). These agents restore antitumor immunity by reactivating suppressed T cells. Although PD-L1 expression is widely used as a predictive biomarker, responses to ICIs can occur even in tumors lacking PD-L1 expression, underscoring the complexity of the tumor immune microenvironment. Ongoing research on the tumor microenvironment aims to achieve a better understanding of cancer progression mechanisms and to improve the assessment of therapeutic efficacy. CASE REPORT We present an 80-year-old man with advanced NSCLC, without any remarkable past medical history, clinically staged as IVB (cT4N3M1c), and demonstrating a PD-L1 tumor proportion score (TPS) of less than 1%. Despite this, he exhibited an excellent response to combination therapy with anti-PD-1, anti-CTLA-4 monoclonal antibodies, and cytotoxic chemotherapy during hospitalization, with manageable adverse events. Notably, pathological analysis revealed marked infiltration of CD3-positive tumor-infiltrating lymphocytes (TILs), averaging 1100/mm². CD4- and CD8-positive TILs were present in equal numbers, suggesting a balanced population of helper and cytotoxic T cells. The patient received a total of 24 cycles of immunotherapy before disease progression was confirmed. CONCLUSIONS This case highlights a striking dissociation between TIL density and PD-L1 expression, suggesting that CD3-positive TILs may reflect underlying immune activity not captured by PD-L1 status alone. Our findings emphasize the need to further explore TIL profiling as a complementary biomarker, particularly in patients treated with anti-PD-1/anti-CTLA-4-containing regimens.