Integrative immune-genomic profiling for identification of treatment-relevant phenotypes association with predicted sensitivity to neoadjuvant chemo-immunotherapy in muscle-invasive bladder cancer.

Abstract

183 Background: Neoadjuvant chemo-immunotherapy is an emerging strategy for muscle-invasive bladder cancer (MIBC), yet responses remain heterogeneous and predictive pretreatment biomarkers are lacking. We performed an integrative immune-genomic analysis of The Cancer Genome Atlas bladder cancer cohort (TCGA-BLCA) to identify biologic phenotypes associated with predicted sensitivity to neoadjuvant chemo-immunotherapy. Methods: Transcriptomic and somatic mutation data were analyzed to evaluate immune infiltration signatures, tumor mutational burden, and DNA damage response (DDR) gene alterations. Immune enrichment metrics were derived from gene expression profiles. In the absence of direct treatment outcomes, tumors were classified into biologically defined immune response phenotypes representing predicted treatment susceptibility. Associations were assessed using descriptive analyses and multivariable Firth penalized logistic regression. Results: Predicted sensitive tumors demonstrated higher global immune infiltration, including elevated ImmuneScore and enrichment of cytotoxic and innate immune signatures. DDR alterations were more frequent in immune-inflamed phenotypes. On multivariable analysis, ImmuneScore remained independently associated with predicted treatment sensitivity (p = 0.003), while other genomic variables showed context-dependent associations. Conclusions: Integrative immune-genomic profiling identifies biologically plausible phenotypes associated with predicted sensitivity to neoadjuvant chemo-immunotherapy in MIBC. Global immune infiltration emerged as a dominant feature of treatment-relevant tumor biology and supports immune-based stratification frameworks requiring prospective validation. Variable  Non-likely responder (n = 251)  Likely responder (n = 260)  p-value  Statistical test  Age, years, Mean (SD)  67.80 (11.06)  68.15 (9.68)  0.707  t = -0.38  Sex, n(%)  -  -  0.002  χ² = 9.43    Female  56 (22.3%)  91 (35.0%)  -  -    Male  195 (77.7%)  169 (65.0%)  -  -  Pathologic tumor stage, n(%)  -  -  0.355  χ² = 0.85    I-II  153 (61.0%)  147 (56.5%)  -  -    III-IV  98 (39.0%)  113 (43.5%)  -  -  DDR status, n(%)  -  -  0.339  χ² = 0.91    DDR-mutated  105 (41.8%)  97 (37.3%)  -  -    DDR-wildtype  146 (58.2%)  163 (62.7%)  -  -  TMB group, n(%)  -  -  0.073  χ² = 3.23    TMB-high  98 (41.7%)  116 (50.4%)  -  -    TMB-low  137 (58.3%)  114 (49.6%)  -  -  ImmuneScore, Mean (SD)  0.04 (0.02)  0.23 (0.18)  <0.001  t = -17.22  StromaScore, Mean (SD)  0.05 (0.08)  0.08 (0.10)  <0.001  t = -4.70  CD8+ T cells, Mean (SD)  -0.41 (0.36)  0.40 (1.23)  <0.001  t = -10.07  NK cells, Mean (SD)  -0.26 (0.02)  0.25 (1.36)  <0.001  t = -5.97  Macrophages, Mean (SD)  0.01 (0.01)  0.06 (0.05)  <0.001  t = -14.90