Perspective on the treatment of non-small cell lung cancer in the context of potential SARS-CoV-2 infection during the pandemic

George  Theodoropoulos; Katerina  Albanis; Medhi  Wangpaichitr

Authors

George Theodoropoulos
Katerina Albanis Department of Veterans Affairs, Miami VA Healthcare System, Research Service, Miami, FL
Medhi Wangpaichitr Department of Veterans Affairs, Miami VA Healthcare System, Research Service, Miami, FL and Department of Surgery, Cardiothoracic Surgery, Miller School of Medicine, University of Miami, Miami, FL

Keywords:

immunosuppressive, infection, lung cancer, metabolism, SARS-CoV-2, treatment, tumor microenvironment

Abstract

SARS-CoV-2 infections are rising at an alarming rate and various aspects of this pandemic must be quickly and adequately addressed in order to enhance effective healthcare delivery and protect at risk populations such as cancer patients. Preventing Covid-19 infection must be a top system wide priority to avoid mortality, and considerable financial and disease burden. Most cancer patients, and in particular those with tumors resistant to chemotherapy are particularly vulnerable to infection. In this review, we connect potential viral infection of patients with lung tumors that have somewhat quiesced the immune response in the tumor microenvironment and categorize target molecules in metabolism that may be used to identify at risk patients leading to more effective treatment regimens; keeping continuity of therapy and disease prevention during a very tumultuous period of time surrounding the pandemic.

References

Beatty, G. L., & Gladney, W. L. (2015). Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res, 21(4), 687-692. DOI: 10.1158/1078-0432.CCR-14-1860

Cascone, T., McKenzie, J. A., Mbofung, R. M., Punt, S., Wang, Z., Xu, C., . . . Peng, W. (2018). Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy. Cell Metab, 27(5), 977-987 e974. DOI: 10.1016/j.cmet.2018.02.024

Chen, G. Y., Chen, C., Wang, L., Chang, X., Zheng, P., & Liu, Y. (2008). Cutting edge: Broad expression of the FoxP3 locus in epithelial cells: a caution against early interpretation of fatal inflammatory diseases following in vivo depletion of FoxP3-expressing cells. J Immunol, 180(8), 5163-5166. DOI: 10.4049/jimmunol.180.8.5163

Chen, M. L., Pittet, M. J., Gorelik, L., Flavell, R. A., Weissleder, R., von Boehmer, H., & Khazaie, K. (2005). Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci U S A, 102(2), 419-424. DOI: 10.1073/pnas.0408197102

Creelan, B. C., Antonia, S., Bepler, G., Garrett, T. J., Simon, G. R., & Soliman, H. H. (2013). Indoleamine 2,3-dioxygenase activity and clinical outcome following induction chemotherapy and concurrent chemoradiation in Stage III non-small cell lung cancer. Oncoimmunology, 2(3), e23428. DOI: 10.4161/onci.23428

Dang, E. V., Barbi, J., Yang, H. Y., Jinasena, D., Yu, H., Zheng, Y., . . . Pan, F. (2011). Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell, 146(5), 772-784. DOI: 10.1016/j.cell.2011.07.033

Davis, I., & Liu, A. (2015). What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics? Expert Rev Neurother, 15(7), 719-721. DOI: 10.1586/14737175.2015.1049999

de Araujo, E. F., Feriotti, C., Galdino, N. A. L., Preite, N. W., Calich, V. L. G., & Loures, F. V. (2017). The IDO-AhR Axis Controls Th17/Treg Immunity in a Pulmonary Model of Fungal Infection. Front Immunol, 8, 880. DOI: 10.3389/fimmu.2017.00880

Doedens, A. L., Phan, A. T., Stradner, M. H., Fujimoto, J. K., Nguyen, J. V., Yang, E., . . . Goldrath, A. W. (2013). Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol, 14(11), 1173-1182. DOI: 10.1038/ni.2714

Ferdinande, L., Decaestecker, C., Verset, L., Mathieu, A., Moles Lopez, X., Negulescu, A. M., . . . Demetter, P. (2012). Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer. Br J Cancer, 106(1), 141-147. DOI: 10.1038/bjc.2011.513

Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003). Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol, 4(4), 330-336. DOI: 10.1038/ni904

Fox, C. J., Hammerman, P. S., & Thompson, C. B. (2005). Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol, 5(11), 844-852. DOI: 10.1038/nri1710

Gao, Y. F., Peng, R. Q., Li, J., Ding, Y., Zhang, X., Wu, X. J., . . . Zhang, X. S. (2009). The paradoxical patterns of expression of indoleamine 2,3-dioxygenase in colon cancer. J Transl Med, 7, 71. DOI: 10.1186/1479-5876-7-71

Guan, W. J., Ni, Z. Y., Hu, Y., Liang, W. H., Ou, C. Q., He, J. X., . . . China Medical Treatment Expert Group for, C. (2020). Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med., 382, 1708-1720. DOI: 10.1056/NEJMoa2002032

Heng, B., Lim, C. K., Lovejoy, D. B., Bessede, A., Gluch, L., & Guillemin, G. J. (2016). Understanding the role of the kynurenine pathway in human breast cancer immunobiology. Oncotarget, 7(6), 6506-6520. DOI: 10.18632/oncotarget.6467

Hidalgo, G. E., Zhong, L., Doherty, D. E., & Hirschowitz, E. A. (2002). Plasma PGE-2 levels and altered cytokine profiles in adherent peripheral blood mononuclear cells in non-small cell lung cancer (NSCLC). Mol Cancer, 1(1), 5. DOI: 10.1186/1476-4598-1-5

Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., . . . Pohlmann, S. (2020). SARS-CoV-2 CellEntry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 181(2), 271-280 e278. DOI: 10.1016/j.cell.2020.02.052

Hori, S., Nomura, T., & Sakaguchi, S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science, 299(5609), 1057-1061. DOI: 10.1126/science.1079490

Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., . . . Cao, B. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 395(10223), 497-506. DOI: 10.1016/S0140-6736(20)30183-5

Jones, R. G., & Thompson, C. B. (2007). Revving the engine: signal transduction fuels T cell activation. Immunity, 27(2), 173-178. DOI: 0.1016/j.immuni.2007.07.008

Kamiya, T., Hatanaka, H., Abe, Y., Kijima, H., Yamazaki, H., Ohnishi, Y., . . . Nakamura, M. (2003). Interleukin-10 expression is closely correlated with the expression of granulocyte-macrophage colony-stimulating factor in non-small cell lung cancer. Anticancer Res, 23(3C), 2909-2913.

Karanikas, V., Speletas, M., Zamanakou, M., Kalala, F., Loules, G., Kerenidi, T., . . . Germenis, A. E. (2008). Foxp3 expression in human cancer cells. J Transl Med, 6, 19. DOI: 10.1186/1479-5876-6-19

Karanikas, V., Zamanakou, M., Kerenidi, T., Dahabreh, J., Hevas, A., Nakou, M., . . . Germenis, A. E. (2007). Indoleamine 2,3-dioxygenase (IDO) expression in lung cancer. Cancer Biol Ther, 6(8), 1258-1262. DOI: 10.4161/cbt.6.8.4446

Liang, W., Guan, W., Chen, R., Wang, W., Li, J., Xu, K., . . . He, J. (2020). Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol, 21(3), 335-337. DOI: 10.1016/S1470-2045(20)30096-6

Liu, H., Shen, Z., Wang, Z., Wang, X., Zhang, H., Qin, J., . . . Sun, Y. (2016). Increased expression of IDO associates with poor postoperative clinical outcome of patients with gastric adenocarcinoma. Sci Rep, 6, 21319. DOI: 10.1038/srep21319

Livingston, E., & Bucher, K. (2020). Coronavirus Disease 2019 (COVID-19) in Italy. JAMA., 323(14), 1335. DOI: 10.1001/jama.2020.4344

Lukassen, S., Chua, R. L., Trefzer, T., Kahn, N. C., Schneider, M. A., Muley, T., . . . Eils, R. (2020). SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. Embo J, e105114. DOI: 10.15252/embj.20105114

Mbongue, J. C., Nicholas, D. A., Torrez, T. W., Kim, N. S., Firek, A. F., & Langridge, W. H. (2015). The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity. Vaccines (Basel), 3(3), 703-729. DOI: 10.3390/vaccines3030703

Miller, K. D., Siegel, R. L., Lin, C. C., Mariotto, A. B., Kramer, J. L., Rowland, J. H., . . . Jemal, A. (2016). Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin, 66(4), 271-289. DOI: 10.3322/caac.21349

Moon, Y. W., Hajjar, J., Hwu, P., & Naing, A. (2015). Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer, 3, 51. DOI: 10.1186/s40425-015-0094-9

Neuner, A., Schindel, M., Wildenberg, U., Muley, T., Lahm, H., & Fischer, J. R. (2002). Prognostic significance of cytokine modulation in non-small cell lung cancer. Int J Cancer, 101(3), 287-292. DOI: https://doi.org/10.1002/ijc.10604

Peters, J. C. (1991). Tryptophan nutrition and metabolism: an overview. Adv Exp Med Biol, 294, 345-358. DOI: 10.1007/978-1-4684-5952-4_32

Platten, M., von Knebel Doeberitz, N., Oezen, I., Wick, W., & Ochs, K. (2014). Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors. Front Immunol, 5, 673. DOI: 10.3389/fimmu.2014.00673

Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Tao, Y., . . . Tian, D. S. (2020). Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis., 71(15), 762-768. DOI: 10.1093/cid/ciaa248

Rizvi, N. A., Mazieres, J., Planchard, D., Stinchcombe, T. E., Dy, G. K., Antonia, S. J., . . . Ramalingam, S. S. (2015). Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol, 16(3), 257-265.DOI: 10.1016/S1470-2045(15)70054-9

Saji, H., Nakamura, H., Awut, I., Kawasaki, N., Hagiwara, M., Ogata, A., . . . Kato, H. (2003). Significance of expression of TGF-beta in pulmonary metastasis in non-small cell lung cancer tissues. Ann Thorac Cardiovasc Surg, 9(5), 295-300.

Schalper, K. A., Carvajal-Hausdorf, D., McLaughlin, J., Altan, M., Velcheti, V., Gaule, P., . . . Rimm, D. L. (2017). Differential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer. Clin Cancer Res, 23(2), 370-378. DOI: 10.1158/1078-0432.CCR-16-0150

Shevach, E. M. (2002). CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol, 2(6), 389-400. DOI: 10.1038/nri821

Shi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., & Chi, H. (2011). HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med, 208(7), 1367-1376. DOI: 10.1084/jem.20110278

Shi, Y., & Massague, J. (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 113(6), 685-700. DOI: 10.1016/s0092-8674(03)00432-x

Sonveaux, P., Vegran, F., Schroeder, T., Wergin, M. C., Verrax, J., Rabbani, Z. N., . . . Dewhirst, M. W. (2008). Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest, 118(12), 3930-3942. DOI: 10.1172/JCI36843

Suzuki, Y., Suda, T., Furuhashi, K., Suzuki, M., Fujie, M., Hahimoto, D., . . . Chida, K. (2010). Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer, 67(3), 361-365. DOI: 10.1016/j.lungcan.2009.05.001

Theate, I., van Baren, N., Pilotte, L., Moulin, P., Larrieu, P., Renauld, J. C., . . . Van den Eynde, B. J. (2015). Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol Res, 3(2), 161-172. DOI: 10.1158/2326-6066.CIR-14-0137

Trujillo, J. A., Sweis, R. F., Bao, R., & Luke, J. J. (2018). T Cell-Inflamed versus Non-T Cell-Inflamed Tumors: A Conceptual Framework for Cancer Immunotherapy Drug Development and Combination Therapy Selection. Cancer Immunol Res, 6(9), 990-1000. DOI: 10.1158/2326-6066.CIR-18-0277

van Baren, N., & Van den Eynde, B. J. (2015). Tryptophan-degrading enzymes in tumoral immune resistance. Front Immunol, 6, 34. DOI: 10.3389/fimmu.2015.00034

Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T., & Veesler, D. (2020). Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell, 181(2), 281-292 e286. DOI: 10.1016/j.cell.2020.02.058

Wang, J. Z., Zhang, R. Y., & Bai, J. (2020). An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients. Int J Cardiol. DOI: 10.1016/j.ijcard.2020.04.009

Wang, X., Dong, H., Li, Q., Li, Y., & Hong, A. (2015). Thioredoxin induces Tregs to generate an immunotolerant tumor microenvironment in metastatic melanoma. Oncoimmunology, 4(9), e1027471. DOI: 10.1080/2162402X.2015.1027471

Wangpaichitr, M., Kandemir, H., Li, Y. Y., Wu, C., Nguyen, D., Feun, L. G., . . . Savaraj, N. (2017). Relationship of Metabolic Alterations and PD-L1 Expression in Cisplatin Resistant Lung Cancer. Cell Dev Biol, 6. DOI: 10.4172/2168-9296.1000183

Wangpaichitr, M., Sullivan, E. J., Theodoropoulos, G., Wu, C., You, M., Feun, L. G., . . . Savaraj, N. (2012). The relationship of thioredoxin-1 and cisplatin resistance: its impact on ROS and oxidative metabolism in lung cancer cells. Mol Cancer Ther, 11(3), 604-615. DOI: 10.1158/1535-7163.MCT-11-0599

Wangpaichitr, M., Wu, C., Li, Y. Y., Nguyen, D. J. M., Kandemir, H., Shah, S., . . . Savaraj, N. (2017). Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer. Oncotarget, 8(30), 49275-49292. DOI: 10.18632/oncotarget.17568

Wangpaichitr, M., Wu, C., You, M., Maher, J. C., Dinh, V., Feun, L. G., & Savaraj, N. (2009). N1,N3-Dimethyl-N1,N3-bis(phenylcarbonothioyl) Propanedihydrazide (Elesclomol) Selectively Kills Cisplatin Resistant Lung Cancer Cells through Reactive Oxygen Species (ROS). Cancers, 1(1), 23-28. DOI: https://doi.org/10.3390/cancers1010023

Wangpaichitr, M., Wu, C. J., Li, Y., Nguyen, D. J. M., Shah, S., Kandemir, H., . . . Savaraj, N. (2017). Exploiting ROS and Metabolic Differences to Kill Cisplatin Resistant Lung Cancer Oncotarget, 8(30), 49275-49292. DOI: 10.18632/oncotarget.17568

Warburg, O. (1956a). On respiratory impairment in cancer cells. Science, 124(3215), 269-270.

Warburg, O. (1956b). On the origin of cancer cells. Science, 123(3191), 309-314. DOI: 10.1126/science.123.3191.309

Woo, E. Y., Yeh, H., Chu, C. S., Schlienger, K., Carroll, R. G., Riley, J. L., . . . June, C. H. (2002). Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol, 168(9), 4272-4276. DOI: 10.4049/jimmunol.168.9.4272

Wu, J. T., Leung, K., Bushman, M., Kishore, N., Niehus, R., de Salazar, P. M., . . . Leung, G. M. (2020). Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China. Nat Med, 26(4), 506-510. DOI: 10.1038/s41591-020-0822-7

Yan, F., Pang, J., Peng, Y., Molina, J. R., Yang, P., & Liu, S. (2016). Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells. PLoS One, 11(9), e0162925. DOI: 10.1371/journal.pone.0162925

Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., & Zhou, Q. (2020). Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science, 367(6485), 1444-1448. DOI: 10.1126/science.abb2762

Zhang, L., Zhu, F., Xie, L., Wang, C., Wang, J., Chen, R., . . . Zhou, M. (2020). Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China. Ann Oncol., 31(7), 894-901 DOI: 10.1016/j.annonc.2020.03.296