Targeting Tumor-Induced Immunosuppression Using Conventional Cancer Therapeutics

Main Article Content

Emma Eriksson Tanja Lövgren Angelica Sara Ingrid Loskog

Abstract

Immunosuppression remains a challenge in the immunotherapy field and needs to be combated to increase survival of patients suffering from cancer. There have been no phase III trials that have in an organized, statistically reliable setting compared immunotherapy outcome with or without so called preconditioning, or metronomic conditioning, in randomized settings. The current view on preconditioning is that it may be used both to reduce tumor load and to reduce suppressive immune cells prior to immunotherapy. For combination treatments, immunotherapy such as checkpoint blockade has shown benefit in combination with chemotherapy even if the major goals of those studies may not have been to condition the patient for a better immune response due to reduced immunosuppression. Nevertheless, there is a need to further enhance the promising effect of cancer immunotherapy. We argue herein that there are several interesting conventional cancer therapeutics to explore for combinational use with immunotherapy to enhance response rates and achieve a longer overall survival of patients. This review will discuss mechanisms of conventional cancer therapeutics of interest for combination therapy. For example, gemcitabine and several tyrosine kinase inhibitors have profound effect on myeloid-derived suppressor cells while tyrosine kinase inhibitors can enhance T cell infiltration into tumors likely due to increased chemokine signaling. Further, cyclophosphamide is well known for its capacity to reduce Tregs and is used to precondition patients prior T cell therapy. How to combine these agents with immunotherapy to further increase patient survival is an important next step in the immunotherapeutic field.

Article Details

How to Cite
ERIKSSON, Emma; LÖVGREN, Tanja; LOSKOG, Angelica Sara Ingrid. Targeting Tumor-Induced Immunosuppression Using Conventional Cancer Therapeutics. Medical Research Archives, [S.l.], v. 9, n. 12, dec. 2021. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2606>. Date accessed: 03 dec. 2022. doi: https://doi.org/10.18103/mra.v9i12.2606.
Section
Review Articles

References

1. Virchow, R. Cellular pathology. As based upon physiological and pathological histology. Lecture XVI-atheromatous affection of arteries. 1858. Nutr Rev. 1989;47:23-25.
2. Starnes, CO. Coley’s toxins. Nature. 1992;360:23.
3. Starnes, CO. Coley’s toxins in perspective. Nature. 1992;357:11-12.
4. Lobo N, Brooks NA, Zlotta AR, Cirillo JD, Boorjian S, Black PC, Meeks JJ, Bivalacqua TJ, Gontero P, Steinberg GD, McConkey D, Bbjuk M, Witjes JA, Kamat AM. 100 years of Bacillus Calmette-Guérin immunotherapy: from cattle to COVIS-19. Mat Rev Urol. 2021;18:611-622.
5. Brandau S, Böhle A. Activation of natural killer cells by Bacillus Calmette-Guerin.
Eur Urol. 2001;39:518-254.
6. Suttmann H, Jacobsen M, Reiss K, Joacham D, Böhle A, Brandau S. Mechanisms of bacillus Calmette-Guerin mediated natural killer cell activation. J Urol. 2004;172:1490-1495.
7. Lim CJ, Nguyen PHD, Wasser M, Kumar P, Lee YH, Nasir NJM, Chua C, Lai L, Hazirah SN, Loh JJH, Khor LY, Yeong J, Lim TKH, Low AWX, Albani S, Chong TW, Chew V. Immunological Hallmarks for Clinical response to BCG in Bladder cancer. Front Immunol. 2021;11:615091.
8. Nishizuka Y, Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science. 1969;166:753-755.
9. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057-1061.
10. Clarke SL, Betts GJ, Plant A, Wright KL, El-Shanawany TM, Harrop R, Torkington J, Rees BI, Williams GT, Gallimore AM, Godkin AJ. CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS One. 2006;1:e129.
11. Viguier M, Lemaitre F, Verola O, Cho MS, Gorochov G, Dubertret L, Bachelez H, Kourilsky P, Ferradini L. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol. 2004;173:1444-1452.
12. Chen YQ, Shi H-Z, Qin X-J, Mo W-N, Liang X-D, Huang Z-X, Yang H-B, Wu C. CD4+CD25+ regulatory T lymphocytes in malignant pleural effusion. Am J Respir Crit Care Med. 2005;172:1434—1439.
13. Brinkrolf P, Landmeier S, Altvater B, Chen C, Pscherer S, Rosemann A, Ranft A, Dirksen U, Juergens H, Rossig C. A high proportion of bone marrow T cells with regulatory phenotype (CD4+CD25hiFoxP3+) in Ewing sarcoma patients is associated with metastatic disease. Int J Cancer. 2009;125:879-886.
14. Loskog A, Ninalga C, Paul-Wetterberg G, de la Torre M, Malmström PU, Tötterman TH. Human bladder carcinoma is dominated by T-regulatory cells and Th1 inhibitory cytokines. J Urol. 2007;177:353-358.
15. Nakata J, Isohashi K, oka Y, Nakajima H, Morimoto S, Fujiki F, Oji Y, Tsuboi A, Kumanogoh A, Hashimoto N, Hatazawa J, Sugiyama H. Imaging assessment of tumor response in the era of immunotherapy. Diagnostics (Basel). 2021;11:1041.
16. Labani-Motlagh A, Ashja-Mahdavi M, Loskog A. The tumor microenvironment: A milieu hindering and obstructing antitumor immune responses. Front Immunol. 2020;11:940.
17. Shevyrev D, Tereshchenko V. Treg heterogeneity, function and hemeostasis. Front Immunol. 2020;10:3100.
18. Dou A, Fang J. Heterogeneous myeloid cells in tumors. Cancers (Basel). 2021;13:3772.
19. Olson, BM, Sullivan JA, Burlingham WJ. Interleukin 35: a key mediator of suppression and the propagation of infectious tolerance. Front Immunol. 2013;4:315.
20. Wing JB, Tanaka A, Sakaguchi S. Human FOXP3(+) regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity. 2019;50:302-316.
21. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162-174.
22. Yu J, Du W, Yan F, Wang Y, Li H, Cao S, Yu W, Shen C, Liu J, Ren X. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol. 2013; 190:3783-3797.
23. Nagaraj S, Gabrilovich DI. Regulation of suppressive function of myeloid-derived suppressor cells by CD4+ T cells. Semin cancer biol. 2012;22:282-288.
24. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23:2346-2357.
25. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26:5233-5239.
26. Kumar A, Watkins R, Vilgelm AE. Cell Therapy With TILs: Training and Taming T Cells to Fight Cancer. Front Immunol. 2021;12:690499.
27. Damuzzo V, Agnoletto L, Leonardi L, Chiumente M, Mengato D, Messori A. Analysis of Survival Curves: Statistical Methods Accounting for the Presence of Long-Term Survivors. Front Oncol. 2019;9:453.
28. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56:641-648.
29. Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, Kamble RT, Bollard CM, Gee AP, Mei Z, Liu H, Grilley B, Rooney CM, Heslop HE, Brenner MK, Dotti G. CD28 costimulation improves expansion and persistence of chimeric antigenreceptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121:1822-1826.
30. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3:95ra73.
31. Enblad G, Karlsson H, Gammelgård G, Wenthe J, Lövgren T, Amini RM, Wikstrom KI, Essand M, Savaldo B, Hallböök H, Höglund M, Dotti G, Brenner MK, Hagberg H, Loskog A. A Phase I/IIa trial using CD19-targeted third-generation CAR T cells for lymphoma and leukemia. Clin Cancer Res. 2018;24:6185-6194.
32. Xu W, Cai J, Li S, Zhang H, Han J, Wen M, Wen J, Gao F. Improving the in vivo presence, distribution, and function of cytotoxic T lymphocytes by inhibiting the tumor immunosuppressive microenvironment. Scand J Immunol. 2013;78:50-60.
33. Green H, Hasmats J, Kupershmidt I, Edsgard D, de Petris L, Lewensohn R, Blackhall F, Vikingsson S, Besse B, Lindgren A, et al: Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities. Clin Cancer Res. 2016;22:366-73
34. Eriksson E, Wenthe J, Irenaeus S, Loskog A, Ullenhag G. Gemcitabine reduces MDSCs, regs and TGFb-1 while resotring the teff/treg ration in patients with pancreatic cancer. J Transl Med. 2016;14:282.
35. Fu BH, Fu ZZ, Meng W, Gu T, Sun XD, Zhang Z: Platelet VEGF and serum TGF-beta1 levels predict chemotherapy response in non-small cell lung cancer patients. Tumour Biol. 2015;36:6477-6483.
36. Tang SN, Fu J, Shankar S, Srivastava RK: EGCG enhances the therapeutic potential of gemcitabine and CP690550 by inhibiting STAT3 signaling pathway in human pancreatic cancer. PLoS One. 2012;7:e31067.
37. Plate JM, Plate AE, Shott S, Bograd S, Harris JE: Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother. 2005;54:915-925.
38. Bang S, Kim HS, Choo YS, Park SW, Chung JB, Song SY: Differences in immune cells engaged in cell-mediated immunity after chemotherapy for far advanced pancreatic cancer. Pancreas. 2006;32:29-36.
39. Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009;15:2148–2157.
40. Xin H, Zhang C, Herrmann A, Du Y, Figlin R, Yu H. Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res. 2009;69:2506–2513.
41. Sayed D, Badrawy H, Gaber N, Khalaf MR. p-Stat3 and bcr/abl gene expression in chronic myeloid leukemia and their relation to imatinib therapy. Leuk Res. 2014;38:243–250.
42. Michels S, Trautmann M, Sievers R, Kindler D, Huss S, Renner M Friedrichs N, Kirfel J, Steiner S, Endl E, Wurst P, Heukamp L, Penzel R, Larsson O, Kawai A, Tanaka S, Sonobe H, Schirmacher P, Mechtersheimer G, Wardelmann E, Büttner R, Hartmann W. SRC signaling is crucial in the growth of synovial sarcoma cells. Cancer Res. 2013;73:2518–28.
43. Tengesdal IW, Dinarello A, Powers NE, Burchill MA, Joosten LAB, Marchetti C, Dinarello CA. Tumor NLRP3-Derived IL-1beta Drives the IL-6/STAT3 Axis Resulting in Sustained MDSC-Mediated Immunosuppression. Front Immunol. 2021;12:661323.
44. Thorn M, Guha P, Cunetta M, Espat NJ, Miller G, Junghans RP, Katz SC. Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases. Cancer Gene Ther. 2016;23:188-198.
45. Yuan C, Ni L, Wu X. activin A activation drives renal fibrosis through the STAT3 signaling pathway. Int J Biochem Cell biol. 2021;134:105950.
46. Seggewiss R, Lore K, Greiner E, Magnusson MK, Price DA, Douek DC, Dunbar CE, Wiestner A. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood. 2005;105:2473–2479.
47. Blake SJ, Bruce Lyons A, Fraser CK, Hayball JD, Hughes TP.Dasatinib suppresses in vitro natural killer cell cytotoxicity. Blood. 2008;111:4415–4416.
48. Appel S, Boehmler A, Gruneback F, Muller MR, Rupf A, Weck MM, Hartmann U, Reichardt VL, Kanz L, Brummendorf TH, Brossart P. Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood. 2004;103:538–544.
49. Chen CI, Maecker HT, Lee PP. Development and dynamics of robust T-cell responses to CML under imatinib treatment. Blood. 2008;111:5342–5349.
50. Rohon P, Porkka K, Mustjoki S. Immunoprofiling of patients with chronic myeloid leukemia at diagnosis and during tyrosine kinase inhibitor therapy. Eur J Haematol. 2010;85:387–398.
51. Mustjoki S, Ekblom M, Arstila TP, Dybedal I, Epling-Burnette PK, Guilhot F, Hjorth-Hansen H, Höglund M, Kovanen P, Laurinolli T, Liesveld J, Paquette R, Pinilla-Ibarz J, Rauhala A, Shah N, Simonsson B, Sinisalo M, Steegmann JL, Stenke L, Porkka K. Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia. 2009;23:1398–1405.
52. Christiansson L, Söderlund S, Mangsbo S, Hjorth-Hansen H, Höglund M, Markevärn B Richter J, Stenke L, Mustjoki S, Loskog A, Olsson-Strömberg U. The tyrosine kinase inhibitors imatinib and dasatinib reduce myeloid suppressor cells and release effector lymphocyte responses. Mol Cancer Ther. 2015;14:1181-1191.
53. Söderlund S, Christiansson L, Persson I, Hjorth-Hansen H, Richter J, Simonsson B, Mustjoki S, Olsson-Strömberg U, Loskog A. Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli. Leuk Res. 2016;50:95-103.
54. Tanaka A, Nishikawa H, Noguchi S, Sugiyama D, Morikawa H, Takeuchi Y, Ha D, Shigeta N, Kitawaki T, Maeda Y, Saito T, Shinohara Y, Kameoka Y, Iwaisako K, Monma F, Ohishi K, Karbach J, Jäger E, Sawada K, Katayama N, Takahashi N, Sakaguchi S. Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells. J Exp Med. 2020;217:e20191009
55. Huang H, Langenkamp E, Georganaki M, Loskog A, Fuchs PD; Dieterich LC; Kreuger J, Dimberg A. VEFG suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-kB -induced endothelial activation. FASEB J. 2015;29:227-238.