Radiologic, Pathologic, and Deep Learning Predictors of Response to Immune Checkpoint Blockade in Renal Cell Carcinoma Patients Undergoing Post-Treatment Nephrectomy

Background Response assessment of primary kidney tumors in the consolidation cytoreductive and neoadjuvant settings offers a unique opportunity to inform postoperative adaptive treatment strategies. Yet, systematic analyses evaluating radiology, pathology, and machine learning are lacking.

We retrospectively identified consecutive renal cell carcinoma (RCC) patients with locoregionally advanced or metastatic RCC who received at least one cycle of ICI-containing doublet therapy prior to nephrectomy at the UTSW Kidney Cancer Program (2017–2024). Radiologic and pathologic features were centrally reviewed and correlated with clinical outcomes: freedom from start of next systemic therapy (FFNT) in cytoreductive patients and metastasis-free survival (MFS) in neoadjuvant patients. Pathologic response to ICI results in tumor cell death and fibrosis creating hypocellular areas and increased immune infiltrate, features we utilized to build Deep learning (DL) models. We leveraged DL models to validate pathologist-assessed regression objectively and quantitate immune infiltrate.

Among 99 patients (cytoreductive nephrectomy {CN}, n=66; neoadjuvant nephrectomy {NaN}, n=33), radiologic tumor shrinkage ≥30% (p=0.0036) and the extent of ICI-induced pathologic regression as assessed by central review (HR 0.97; CI 0.95-0.99; p=0.0023) and by DL (HR 0.96; CI 0.93-0.99; p=0.0041), but not coagulative necrosis, were significantly associated with prolonged FFNT, with similar trends in neoadjuvant cohort. Multivariable Cox regression analyses showed pathologic regression, DL-derived extent of immune infiltrate and tumor largest dimension at nephrectomy to be independent predictors of FFNT.

This study provides, for the first time, an integrated, quantitative framework of post-ICI response in RCC. Our data suggests that immune-mediated pathologic regression changes differ from coagulative necrosis, an indicator of poor prognosis. Our findings provide a blueprint for complementary role of radiology and pathology evaluation of post ICI-nephrectomy specimens that if validated prospectively, could guide adaptive approaches and clinical trial design for ICI-based therapies in kidney cancer and beyond. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by the NIH sponsored Kidney Cancer SPORE grant (P50CA196516) and endowment from Jan and Bob Pickens Distinguished Professorship in Medical Science and Brock Fund for Medical Science Chair in Pathology. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UT Southwestern Review Board (STU 022015-015) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present work are contained in the manuscript