TY - JOUR
T1 - Tumor MHC Class I Expression Associates with Intralesional IL2 Response in Melanoma
AU - Pourmaleki, Maryam
AU - Jones, Caitlin J.
AU - Ariyan, Charlotte E.
AU - Zeng, Zheng
AU - Pirun, Mono
AU - Navarrete, Daniel A.
AU - Li, Yanyun
AU - Zhang, Mianlei
AU - Nandakumar, Subhiksha
AU - Campos, Carl
AU - Nadeem, Saad
AU - Klimstra, David S.
AU - Temple-Oberle, Claire F.
AU - Brenn, Thomas
AU - Lipson, Evan J.
AU - Schenk, Kara M.
AU - Stein, Julie E.
AU - Taube, Janis M.
AU - White, Michael G.
AU - Traweek, Raymond
AU - Wargo, Jennifer A.
AU - Kirkwood, John M.
AU - Gasmi, Billel
AU - Goff, Stephanie L.
AU - Corwin, Alex D.
AU - McDonough, Elizabeth
AU - Ginty, Fiona
AU - Callahan, Margaret K.
AU - Schietinger, Andrea
AU - Socci, Nicholas D.
AU - Mellinghoff, Ingo K.
AU - Hollmann, Travis J.
N1 - Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/3
Y1 - 2022/3
N2 - Cancer immunotherapy can result in lasting tumor regression, but predictive biomarkers of treatment response remain ill-defined. Here, we performed single-cell proteomics, transcriptomics, and genomics on matched untreated and IL2 injected metastases from patients with melanoma. Lesions that completely regressed following intralesional IL2 harbored increased fractions and densities of nonproliferating CD8þ T cells lacking expression of PD-1, LAG-3, and TIM-3 (PD-1-LAG-3-TIM-3-). Untreated lesions from patients who subsequently responded with complete eradication of all tumor cells in all injected lesions (individuals referred to herein as “extreme responders”) were characterized by proliferating CD8þ T cells with an exhausted phenotype (PD-1þLAG-3þTIM-3þ), stromal B-cell aggregates, and expression of IFNg and IL2 response genes. Loss of membranous MHC class I expression in tumor cells of untreated lesions was associated with resistance to IL2 therapy. We validated this finding in an independent cohort of metastatic melanoma patients treated with intralesional or systemic IL2. Our study suggests that intact tumor-cell antigen presentation is required for melanoma response to IL2 and describes a multidimensional and spatial approach to develop immuno-oncology biomarker hypotheses using routinely collected clinical biospecimens.
AB - Cancer immunotherapy can result in lasting tumor regression, but predictive biomarkers of treatment response remain ill-defined. Here, we performed single-cell proteomics, transcriptomics, and genomics on matched untreated and IL2 injected metastases from patients with melanoma. Lesions that completely regressed following intralesional IL2 harbored increased fractions and densities of nonproliferating CD8þ T cells lacking expression of PD-1, LAG-3, and TIM-3 (PD-1-LAG-3-TIM-3-). Untreated lesions from patients who subsequently responded with complete eradication of all tumor cells in all injected lesions (individuals referred to herein as “extreme responders”) were characterized by proliferating CD8þ T cells with an exhausted phenotype (PD-1þLAG-3þTIM-3þ), stromal B-cell aggregates, and expression of IFNg and IL2 response genes. Loss of membranous MHC class I expression in tumor cells of untreated lesions was associated with resistance to IL2 therapy. We validated this finding in an independent cohort of metastatic melanoma patients treated with intralesional or systemic IL2. Our study suggests that intact tumor-cell antigen presentation is required for melanoma response to IL2 and describes a multidimensional and spatial approach to develop immuno-oncology biomarker hypotheses using routinely collected clinical biospecimens.
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U2 - 10.1158/2326-6066.CIR-21-1083
DO - 10.1158/2326-6066.CIR-21-1083
M3 - Article
C2 - 35013003
AN - SCOPUS:85125883287
SN - 2326-6066
VL - 10
SP - 303
EP - 313
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 3
ER -