Loss of PTEN promotes resistance to T cell-mediated immunotherapy

By Weiyi Peng, J. Chen, Chengwen Liu, Shruti Malu, C. Creasy, M. Tetzlaff, Chunyu Xu, Jodi A. McKenzie, Chunlei Zhang, Xiaoxuan Liang and 34 more. Cancer Discovery, 2015

1,336 citations recorded by the source corpus.

T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. We show that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell-mediated tumor killing and decreases T cell trafficking into tumors. In patients, PTEN loss correlates with decreased T cell infiltration at tumor sites, reduced likelihood of successful T cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T cell infiltration in tumors, and inhibited autophagy, which decreased T cell-mediated cell death. Treatment with a selective PI3Kβ inhibitor improved the efficacy of both anti-PD-1 and anti-CTLA4 antibodies in murine models. Together these findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K-AKT pathway inhibitors.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/34e1d97fa9ee4c4bc340805bc5b8734d6ff6e7b9

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In Immunology

1. J. Wolchok
2. Ton N. Schumacher
3. M. Hellmann
4. A. Schoenfeld
5. K. Flaherty
6. D. Thommen
7. S. Spranger
8. I. Melero

In Molecular Biology

1. S. Baylin
2. D. Fruman
3. B. Hopkins
4. R. DePinho
5. R. Abraham
6. Honyin Chiu
7. S. Bagrodia
8. Lewis C. Cantley

In Oncology

1. J. Wolchok
2. M. Hellmann
3. Ton N. Schumacher
4. K. Flaherty
5. D. Thommen
6. A. Schoenfeld
7. S. Spranger
8. D. Barbie

Citations in the corpus

• Integrative molecular and clinical modeling of clinical outcomes to PD-1 blockade in metastatic melanoma patients (2019, neutral): “…including tumor mutation and neoantigen burden (TMB) 8-11 , immunohistological detection of PD-L1/CD8 12 , and genetic alterations affecting antigen presentation 13,14 , interferon-gamma signalling pathways 15 , alternative survival and proliferation pathways 13,16,17 , and aneuploidy 18,19 .”
• Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “…levels of CCL2 and VEGF, diminished infiltration of T cells, and resistance to PD-1 blockade 10 www.bjcancer.com | DOI:10.1038/bjc.2017.434 (Peng et al, 2016), and biallelic PTEN loss was recently reported in an isolated non-responding lesion in a patient with near complete response to…”
• Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition (2021, neutral): “…2018), B2M mutations (Gettinger et al., 2017), JAK1/JAK2 mutations (Shin et al., 2017), KRAS and TP53mutations (Aredo et al., 2019), PTENmutations (Peng et al., 2016), RTKmutations (Anagnostou et al., 2020), STK11mutations (Aredo et al., 2019), BAP1mutations (Shrestha et al., 2019), CD8A (Tumeh…”
• Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma (2016, neutral): “and CCL2 expression was associated with innate anti-PD-1 resistance (Peng et al., 2015).”
• T Cell Dysfunction in Cancer (2018, background): “Of note, melanoma patients with tumors that display PTEN loss showed a significantly lower reduction in tumor burden upon PD-1 treatment (Peng et al., 2016).”
• Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “…preclinical models, loss of the tumor suppressor PTEN, which is critical in the regulation of PI3K activity, increases expression of immunosuppressive cytokines and decrease T cell effector IFN-γ leading to inhibition of T-cell mediated infiltration and immunity (Peng et al., 2016).”
• A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade (2018, neutral): “Melanoma cell line 2686 and matched TILs ( = co-culture) were derived from a male patient (age unknown) and provided by MDACC (Peng et al., 2016).”
• Advances in immunotherapy for hepatocellular carcinoma (2021, background): “I.M. receives funding from MINECO SAF2014-52361-R and SAF 2017- 83267-C2-1R; Worldwide Cancer Research Grant (15-1146); the Asociacion Española Contra el Cancer (AECC) Foundation under grant GCB15152947MELE; and the European Union’s Horizon 2020 Program (grant agreement no. 635122 PROCROP).”
• The PI3K pathway in human disease (2017, positive): “Immunotherapy resistance was recently linked to tumor-cell-autonomous PI3K pathway activation (Peng et al., 2016).”
• STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma (2018, background): “KL KP K-only 54(0) 56(0) 64(0) 25(5) 36(2) 45(4) 10(12) 19(14) 27(18) 4(16) 4(26) 4(34) 2(17) 1(29) 1(37) 1(18) 1(29) 1(37) 1(18) 1(29) 1(37) 0(19) 1(29) 0(38) 0(19) 0(30) 0(38) KL KRASSTK11”