Research progress in screening non-small cell lung cancer patients who will benefit from immunotherapy

doi:10.3969/j.issn.1674-8115.2021.08.020

Abstract

Abstract:

The application of immune checkpoint inhibitors (ICIs) has brought the treatment of non-small cell lung cancer (NSCLC) into a brand-new age. However, not all patients with NSCLC can benefit from ICIs, and there is currently no good standard for screening the beneficiaries, which provides difficulties for ICIs to bring greater benefits to patients. Therefore, it is quite important to explore suitable biomarkers that can predict the level of patients′ response to ICIs. Due to the complexity of the mechanism of the action of ICIs, many links involved in the tumor immune response, including tumor-related cells, molecules or genetic characteristics, may affect the patients' response to ICIs, and may also have the ability to predict the level of NSCLC patients' response to ICIs at the same time. Currently many studies are exploring the clinical significance and limitations of existing biomarkers, struggling to explore potential emerging biomarkers and combine multiple biomarkers for a more reliable predicting model, in order to bring precise treatment to patients with NSCLC. This article is a review based on the latest research results. It summarizes the current application and research progress of biomarkers to screen NSCLC candidates who will benefit from immunotherapy.

Key words: non-small-cell lung cancer (NSCLC), immunotherapy, immune checkpoint inhibitor (ICI), biomarker

CLC Number:

R734.2

Xu-xin-yi LING, Yao ZHANG, Hua ZHONG. Research progress in screening non-small cell lung cancer patients who will benefit from immunotherapy[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(8): 1114-1119.

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References 44

1	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424.
2	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132.
3	Ettinger DS, Wood DE, Aisner DL, et al. Non-small cell lung cancer clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2004, 2(2): 94.
4	Ettinger DS, Wood DE, Aggarwal C, et al. NCCN guidelines insights: non-small cell lung cancer, version 1.2020[J]. J Natl Compr Canc Netw, 2019, 17(12): 1464-1472.
5	Brody R, Zhang Y, Ballas M, et al. PD-L1 expression in advanced NSCLC: insights into risk stratification and treatment selection from a systematic literature review[J]. Lung Cancer, 2017, 112: 200-215.
6	Fehrenbacher L, von Pawel J, Park K, et al. Updated efficacy analysis including secondary population results for OAK: a randomized phase Ⅲ study of atezolizumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer[J]. J Thorac Oncol, 2018, 13(8): 1156-1170.
7	Paz-Ares L, Spira A, Raben D, et al. Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage Ⅲ non-small-cell lung cancer in the PACIFIC trial[J]. Ann Oncol, 2020, 31(6): 798-806.
8	Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[J]. N Engl J Med, 2015, 373(2): 123-135.
9	Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J]. N Engl J Med, 2015, 373(17): 1627-1639.
10	Mazzaschi G, Madeddu D, Falco A, et al. Low PD-1 expression in cytotoxic CD8⁺ tumor-infiltrating lymphocytes confers an immune-privileged tissue microenvironment in NSCLC with a prognostic and predictive value[J]. Clin Cancer Res, 2018, 24(2): 407-419.
11	Thommen DS, Koelzer VH, Herzig P, et al. A transcriptionally and functionally distinct PD-1⁺ CD8⁺ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade[J]. Nat Med, 2018, 24(7): 994-1004.
12	Gennen K, Käsmann L, Taugner J, et al. Prognostic value of PD-L1 expression on tumor cells combined with CD8+ TIL density in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy[J]. Radiat Oncol, 2020, 15(1): 5.
13	Tokito T, Azuma K, Kawahara A, et al. Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage Ⅲ non-small cell lung cancer patients receiving concurrent chemoradiotherapy[J]. Eur J Cancer, 2016, 55: 7-14.
14	Lin ZY, Gu JC, Cui XX, et al. Deciphering microenvironment of NSCLC based on CD8+ TIL density and PD-1/PD-L1 expression[J]. J Cancer, 2019, 10(1): 211-222.
15	Mazzaschi G, Facchinetti F, Missale G, et al. The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC[J]. Lung Cancer, 2019, 127: 153-163.
16	Cho YH, Choi MG, Kim DH, et al. Natural killer cells as a potential biomarker for predicting immunotherapy efficacy in patients with non-small cell lung cancer[J]. Target Oncol, 2020, 15(2): 241-247.
17	Bianco A, Perrotta F, Barra G, et al. Prognostic factors and biomarkers of responses to immune checkpoint inhibitors in lung cancer[J]. Int J Mol Sci, 2019, 20(19): E4931.
18	Syed Khaja AS, Toor SM, El Salhat H, et al. Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment[J]. Oncotarget, 2017, 8(20): 33159-33171.
19	Syed Khaja AS, Toor SM, El Salhat H, et al. Intratumoral FoxP3⁺Helios⁺ regulatory T cells upregulating immunosuppressive molecules are expanded in human colorectal cancer[J]. Front Immunol, 2017, 8: 619.
20	Wu SP, Liao RQ, Tu HY, et al. Stromal PD-L1-positive regulatory T cells and PD-1-positive CD8-positive T cells define the response of different subsets of non-small cell lung cancer to PD-1/PD-L1 blockade immunotherapy[J]. J Thorac Oncol, 2018, 13(4): 521-532.
21	Weber R, Fleming V, Hu XY, et al. Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors[J]. Front Immunol, 2018, 9: 1310.
22	Prendergast GC, Smith C, Thomas S, et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer[J]. Cancer Immunol Immunother, 2014, 63(7): 721-735.
23	Brochez L, Chevolet I, Kruse V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy[J]. Eur J Cancer, 2017, 76: 167-182.
24	Liu M, Wang X, Wang L, et al. Targeting the IDO1 pathway in cancer: from bench to bedside[J]. J Hematol Oncol, 2018, 11(1): 100.
25	Botticelli A, Cerbelli B, Lionetto L, et al. Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC?[J]. J Transl Med, 2018, 16(1): 219.
26	Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer[J]. Science, 2015, 348(6230): 124-128.
27	Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden[J]. N Engl J Med, 2018, 378(22): 2093-2104.
28	Wu YF, Xu JM, Du CL, et al. The predictive value of tumor mutation burden on efficacy of immune checkpoint inhibitors in cancers: a systematic review and meta-analysis[J]. Front Oncol, 2019, 9: 1161.
29	McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade[J]. Science, 2016, 351(6280): 1463-1469.
30	Oya Y, Kuroda H, Nakada T, et al. Efficacy of immune checkpoint inhibitor monotherapy for advanced non-small-cell lung cancer with ALK rearrangement[J]. Int J Mol Sci, 2020, 21(7): E2623.
31	Gainor JF, Shaw AT, Sequist LV, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis[J]. Clin Cancer Res, 2016, 22(18): 4585-4593.
32	Dong ZY, Zhang JT, Liu SY, et al. EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer[J]. Oncoimmunology, 2017, 6(11): e1356145.
33	Kim JH, Kim HS, Kim BJ. Prognostic value of KRAS mutation in advanced non-small-cell lung cancer treated with immune checkpoint inhibitors: a meta-analysis and review[J]. Oncotarget, 2017, 8(29): 48248-48252.
34	Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma[J]. Cancer Discov, 2018, 8(7): 822-835.
35	Kauffmann-Guerrero D, Tufman A, Kahnert K, et al. Response to checkpoint inhibition in non-small cell lung cancer with molecular driver alterations[J]. Oncol Res Treat, 2020, 43(6): 289-298.
36	Higgs BW, Morehouse CA, Streicher K, et al. Interferon gamma messenger RNA signature in tumor biopsies predicts outcomes in patients with non-small cell lung carcinoma or urothelial cancer treated with durvalumab[J]. Clin Cancer Res, 2018, 24(16): 3857-3866.
37	Ayers M, Lunceford J, Nebozhyn M, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade[J]. J Clin Invest, 2017, 127(8): 2930-2940.
38	Danaher P, Warren S, Lu RZ, et al. Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): results from The Cancer Genome Atlas (TCGA)[J]. J Immunother Cancer, 2018, 6(1): 63.
39	Mandal R, Chan TA. Personalized oncology meets immunology: the path toward precision immunotherapy[J]. Cancer Discov, 2016, 6(7): 703-713.
40	Dudley JC, Lin MT, Le DT, et al. Microsatellite instability as a biomarker for PD-1 blockade[J]. Clin Cancer Res, 2016, 22(4): 813-820.
41	Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer[J]. J Clin Oncol, 2018, 36(8): 773-779.
42	Rizvi H, Sanchez-Vega F, La K, et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing[J]. J Clin Oncol, 2018, 36(7): 633-641.
43	Lee JS, Ruppin E. Multiomics prediction of response rates to therapies to inhibit programmed cell death 1 and programmed cell death 1 ligand 1[J]. JAMA Oncol, 2019, 5(11): 1614-1618.
44	Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure)[J]. Ann Oncol, 2016, 27(8): 1492-1504.

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