Human Papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy, with radiotherapy, alone or combined with immune checkpoint inhibitors, often failing to achieve durable disease control. Here, by conducting longitudinal multi-omic analyses of pre- and post-radiation biopsies from patients receiving a pre-operative hypofractionated radiation regimen, we uncover that radiation rapidly depletes a subpopulation of tumor-infiltrating lymphocytes (TIL), characterized by a proliferative, cytotoxic, and tissue-resident gene signature (T^Prolif_Tox). We provide multi-dimensional evidence for tumor antigen-specificity of T^Prolif_Tox clonotypes and show that post-radiation tumors are instead repopulated by regulatory and non-specific clones. Finally, TIL depletion correlates with radiorecurrent disease after conventional radiation, emphasizing the potential impact of radiation-induced TIL loss regardless of fractionation. Thus, this study provides key insights into radiotherapy-induced alterations in the immune microenvironment that drive immunologic radioresistance and proposes restoring tumor antigen-specific T cell clonotypes as a strategy to improve radioimmunotherapy responses in HNSCC.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is a rare, aggressive subtype of non-Hodgkin lymphoma with no defining immunophenotypic or genetic signature. Extranodal involvement is common, but extensive infiltration without lymphadenopathy is rare. A 69-year-old man presented with progressive cardiomyopathy and conduction disease, without systemic symptoms or imaging evidence of malignancy. Workup revealed an atypical T-cell infiltrate on endomyocardial biopsy, but peripheral blood flow cytometry and imaging were unrevealing. Diagnosis remained uncertain during life. The patient rapidly deteriorated and died. Autopsy revealed diffuse T-cell infiltration in the heart, kidneys, and adrenal gland. Immunohistochemistry was suspicious for lymphoma. Despite biopsy findings, incomplete staging and lack of definitive clonal markers delayed diagnosis. Final diagnosis of PTCL-NOS was made. This case presents cardiac-predominant PTCL-NOS with multiorgan infiltration and no lymphadenopathy. In cases of unexplained cardiomyopathy, endomyocardial biopsy is critical, and malignancy must be considered, even without systemic signs.