Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Au, Lewis; Hatipoglu, Emine; Massy, Marc Robert de; Litchfield, Kevin; Beattie, Gordon; Rowan, Andrew; Schnidrig, Désirée; Thompson, R. Houston; Byrne, Fiona; Horswell, Stuart; Fotiadis, Nicos; Hazell, Steve; Nicol, David; Shepherd, Scott T.C.; Fendler, Annika; Mason, Robert M.; Rosario, Lyra Del; Edmonds, Kim; Lingard, Karla; Sarker, Sarah; Mangwende, Mary; Carlyle, Eleanor; Attig, Jan; Joshi, Kroopa; Uddin, Imran; Becker, Pablo D.; Sunderland, Mariana Werner; Akarca, Ayse U.; Puccio, Ignazio; Yang, William W.; Lund, Tom; Dhillon, Kim; Vásquez, Marcos; Ghorani, Ehsan; Xu, Hang; Spencer, Charlotte; López, José I.; Gréen, Anna; Mahadeva, Ula; Borg, Elaine; Mitchison, Miriam; Proctor, Ian; Falzon, Mary; Pickering, Lisa; Furness, Andrew J.S.; Reading, James L.; Salgado, Roberto; Marafioti, Teresa; Jamal‐Hanjani, Mariam; Abbosh, Chris; Shiu, Kai-Keen; Bridgewater, John; Hochhauser, Daniel; Förster, Martin; Lee, Siow Ming; Ahmad, Tanya; Papadatos-Pastos, Dionysis; Janes, Sam M.; Loo, Peter Van; Enfield, Katey S.S.; McGranahan, Nicholas; Huebner, Ariana; Beck, Stephan; Parker, Peter J.; Walczak, Henning; Enver, Tariq; Hynds, Robert E.; Sinclair, Ron; Lok, Chi-wah; Rhodes, Zoe; Moore, David A.; Khiroya, Reena; Trevisan, Giorgia; Ellery, Peter; Linch, Mark; Brandner, Sebastian; Hiley, Crispin; Veeriah, Selvaraju; Razaq, Maryam; Shaw, Heather; Attard, G.; Akther, Mita Afroza; Naceur-Lombardelli, Cristina; Manzano, Lizi; Al-Bakir, Maise; Summan, Simranpreet; Kanu, Nnenna; Ward, Sophie; Asghar, Uzma; Lim, Emilia L.; Gishen, Faye; Tookman, Adrian; Stone, Paddy; Stirling, Caroline; Hunter, Nikki; Vaughan, Sarah; Spain, Lavinia; Yan, Haixi; Shum, Ben; Yousaf, Nadia; Popat, Sanjay; Curtis, Olivia; Stamp, Gordon; Toncheva, Antonia; Nye, Emma; Murra, Aida; Korteweg, Justine; Josephs, Debra H.; Chandra, Ashish; Spicer, James; Stewart, Ruby M.; Iredale, Lara-Rose; Mackay, Tina; Deakin, Ben; Enting, Debra; Rudman, Sarah; Ghosh, Sharmistha; Karapagniotou, Lena; Pintus, Elias; Tutt, Andrew N.J.; Howlett, Sarah; Michalarea, Vasiliki; Brenton, James D.; Caldas, Carlos; Fitzgerald, Rebecca; Jimenez-Linan, Merche; Provenzano, Elena; Cluroe, Alison D.; Stewart, Grant D.; Watts, Colin; Gilbertson, Richard J.; McDermott, Ultan; Tavaré, Simon; Beddowes, Emma; Roxburgh, Patricia; Biankin, Andrew V.; Chalmers, Anthony J.; Fraser, Sioban; Oien, Karin A.; Kidd, Andrew; Blyth, Kevin G.; Krebs, Matt; Blackhall, Fiona; Summers, Yvonne; Dive, Caroline; Marais, Richard; Gomes, Fábio; Carter, Mat; Dransfield, Jo; Quesne, John Le; Fennell, Dean A.; Shaw, Jacqui A.; Naidu, Babu; Baijal, Shobhit; Tanchel, Bruce; Langman, Gerald; Robinson, Andrew; Collard, Martin; Cockcroft, Peter D.; Ferris, Charlotte; Bancroft, Hollie; Kerr, Amy; Middleton, Gary; Webb, Joanne; Kadiri, Salma; Colloby, P.; Olisemeke, Bernard; Wilson, Rodelaine; Tomlinson, Ian; Jogai, Sanjay; Ottensmeier, Christian; Harrison, David J.; Loda, Massimo; Flanagan, Adrienne M.; McKenzie, Mairead; Hackshaw, Allan; Ledermann, Jonathan A.; Chan, Kitty S.; Sharp, Abby; Farrelly, Laura; Bridger, Hayley; Kassiotis, George; Chain, Benny; Larkin, James; Swanton, Charles; Quezada, Sergio A.; Turajlic, Samra; Challacombe, Ben; Chowdhury, Simon; Drake, William; Fernando, A.; Harrison-Phipps, Karen; Hill, Peter; Horsfield, Catherine; O’Brien, Tim; Olsburgh, Jonathon; Polson, Alexander; Varia, Mary; Verma, Hema

doi:10.1016/j.ccell.2021.10.001

Cited by 167 publications

(118 citation statements)

References 154 publications

(218 reference statements)

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“…We found that these genes are generally associated with immune responses, including those mediated by B cells and lymphocytes. Similar findings have been reported by Au et al [2021] in the context of clear cell renal cell carcinoma patients' therapeutic responses to nivolumab, another immune checkpoint inhibitor. Now, having learned of potentially predictive biomarkers, we assessed how well they delineate patient sub-populations in the IMmotion 151 study.…”

Section: Application To Immotion Trialssupporting

confidence: 87%

A Flexible Approach for Predictive Biomarker Discovery

Boileau,

Qi,

van der Laan

et al. 2022

Preprint

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An endeavor central to precision medicine is predictive biomarker discovery; they define patient sub-populations which stand to benefit most, or least, from a given treatment. The identification of these biomarkers is often the byproduct of the related but fundamentally different task of treatment rule estimation. Using treatment rule estimation methods to identify predictive biomarkers in clinical trials where the number of covariates exceeds the number of participants often results in high false discovery rates. The higher than expected number of false positives translates to wasted resources when conducting follow-up experiments for drug target identification and diagnostic assay development. Patient outcomes are in turn negatively affected. We propose a variable importance parameter for directly assessing the importance of potentially predictive biomarkers, and develop a flexible nonparametric inference procedure for this estimand. We prove that our estimator is double-robust and asymptotically linear under loose conditions on the data-generating process, permitting valid inference about the importance metric. The statistical guarantees of the method are verified in a thorough simulation study representative of randomized control trials with moderate and high-dimensional covariate vectors. Our procedure is then used to discover predictive biomarkers from among the tumor gene expression data of metastatic renal cell carcinoma patients enrolled in recently completed clinical trials. We find that our approach more readily discerns predictive from non-predictive biomarkers than procedures whose primary purpose is treatment rule estimation. An open-source software implementation of the methodology, the uniCATE R package, is briefly introduced.

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Section: Application To Immotion Trialssupporting

confidence: 87%

A Flexible Approach for Predictive Biomarker Discovery

Boileau,

Qi,

van der Laan

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Since multiregional molecular genetic studies have largely been performed without consideration of morphology, the investigation regarding the correlation between histologic immune status and underlying genomes has been limited [ 8 ]. Genetic analysis and multiplex immunofluorescence/immunohistochemical staining remain challenging in routine clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Histologic-Based Tumor-Associated Immune Cells Status in Clear Cell Renal Cell Carcinoma Correlates with Gene Signatures Related to Cancer Immunity and Clinical Outcomes

et al. 2022

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The three-tier immunophenotype (desert, excluded, and inflamed) and the four-tier immunophenotype (cold, immunosuppressed, excluded, and hot) have been linked to prognosis and immunotherapy response. This study aims to evaluate whether immunophenotypes of clear cell renal cell carcinoma, identified on hematoxylin and eosin-stained slides, correlate with gene expression signatures related to cancer immunity, and clinical outcomes. We evaluated tumor-associated immune cells (TAICs) status using three methodologies: three-tier immunophenotype based on the location of TAICs, four-tier immunophenotype considering both the location and degree of TAICs and inflammation score focusing only on the degree of TAICs, using a localized clear cell renal cell carcinoma cohort (n = 436) and The Cancer Genome Atlas (TCGA)-KIRC cohort (n = 162). We evaluated the association of the TAICs status assessed by three methodologies with CD8 and PD-L1 immunohistochemistry and immune gene expression signatures by TCGA RNA-sequencing data. All three methodologies correlated with immunohistochemical and immune gene expression signatures. The inflammation score and the four-tier immunophenotype showed similarly higher accuracy in predicting recurrence-free survival and overall survival compared to the three-tier immunophenotype. In conclusion, a simple histologic assessment of TIACs may predict clinical outcomes and immunotherapy responses.

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“…Additionally, lymphocytes were identified in the fibrovascular septae with foci of lymphovascular invasion on histopathologic investigation. This hypothesis-generating data may suggest that further study of these TCF1+ stem-like T cells and antigen presenting niches may reveal a prognostic and predictive biomarker for tRCC patients treated with ICI, especially given that recent reports have associated TCF1 enrichment with response to ICI in other RCC subtypes ( 10 ). While this case report is only a preliminary view into the role of TCF1+ CD8 T cells in the response to tRCC, and in RCC in general, it provides an interesting and important foundation for future, more comprehensive study into these cells as both a biomarker of and as a key mechanistic player in the response to ICI in RCC.…”

Section: Discussionmentioning

confidence: 87%

“…We also present immunofluorescence (IF) imaging and histopathologic staining of the patient's primary tumor specimen, wherein we specifically probe for the presence of TCF1+ CD8 T cells. The importance of these TCF1+ CD8 T cells for the endogenous immune response to RCC has been demonstrated (4), and others have reported a critical role for these TCF1+ cells in the response to ICI in other tumor types (5)(6)(7)(8)(9), but the role of these cells in the response to ICI has been suggested (10), but not definitively established in RCC, particularly in rare subsets of RCC such as tRCC.…”

Section: Introductionmentioning

confidence: 99%

Case Report: Exceptional Response to Nivolumab Plus Ipilimumab in a Young Woman With TFE3-SFPQ Fusion Translocation-Associated Renal Cell Carcinoma

et al. 2021

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Translocation-associated renal cell carcinoma (tRCC) is a rare, aggressive malignancy that primarily affects children and young adults. There is no clear consensus on the most effective treatment for tRCC and there are no biomarkers of response to treatments in these patients. We present a case of a 23 year-old female with metastatic tRCC to the lungs who was started on treatment with nivolumab and ipilimumab. She had a complete radiographic response to treatment and has been progression-free for over 18 months. Immunofluorescence imaging performed on the baseline primary tumor sample showed significant intratumoral immune infiltration. Importantly, these cells are present in niches characterized by TCF1+ CD8+ T cells. Histopathologic investigation showed the presence of lymphocytes in the fibrovascular septae and foci of lymphovascular invasion. Furthermore, lymphovascular invasion and intratumor niches with TCF1+ CD8+ T cells may predict a favorable response to treatment with nivolumab and ipilimumab. These findings have significant clinical relevance given that immune checkpoint inhibitors are approved for several malignancies and predictive biomarkers for response to treatment are lacking. Importantly, the identification of these TCF1+ CD8+ T cells may guide treatment for patients with tRCC, which is a rare malignancy without a consensus first-line treatment option.

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Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Cited by 167 publications

References 154 publications

A Flexible Approach for Predictive Biomarker Discovery

A Flexible Approach for Predictive Biomarker Discovery

Histologic-Based Tumor-Associated Immune Cells Status in Clear Cell Renal Cell Carcinoma Correlates with Gene Signatures Related to Cancer Immunity and Clinical Outcomes

Case Report: Exceptional Response to Nivolumab Plus Ipilimumab in a Young Woman With TFE3-SFPQ Fusion Translocation-Associated Renal Cell Carcinoma

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