Tumor-infiltrating lymphocytes: opportunities to use their potential in clinical practice in breast cancer

Abstract

Tumor-infiltrating lymphocytes are currently considered as a prognostic biomarker of cancer patient survival and response to therapy, as well as a target for immunotherapy. However, tumor-infiltrating lymphocytes are only part of the tumor microenvironment, which consists of cellular and cytokine components. The cellular component also includes tumor-associated macrophages, neutrophils, fibroblasts and other cells. The cytokine component is represented by the products of the activity of all cells of the microenvironment, as well as tumor cells.

This review examines various subpopulations of tumor-infiltrating lymphocytes, shows their interaction with tumor cells and other cell populations of the tumor microenvironment, and also describes the potential for clinical use of this cell population as a biomarker for predicting clinical outcomes and the possibility of their use to determine the most effective treatment for breast cancer.

Obtaining new data on the previously poorly studied components of the tumor microenvironment and tumor-infiltrating lymphocytes, as well as the formation of ideas about the mutual influence of tumor microenvironment cells and tumor cells open up the prospect of developing innovative models of therapy. One of the modern directions is the search for molecular mechanisms of maintaining the antitumor activity of tumor-infiltrating lymphocytes, as well as the polarization of cells in the tumor microenvironment. Advances in the field of molecular oncology will make it possible to reduce the mortality rate of cancer patients to minimal levels while maintaining or even improving their standard of living.

Keywords

tumor microenvironment studies / tumor-infiltrating lymphocytes / breast cancer

References

[1] Annaratone L, Cascardi E, Vissio E, et al. The multifaceted nature of tumor microenvironment in breast carcinomas. Pathobiology. 2020;87(2):125–142. doi: 10.1159/000507055

[2] Annaratone L., Cascardi E., Vissio E., et al. The multifaceted nature of tumor microenvironment in breast carcinomas // Pathobiology. 2020. Vol. 87, N 2. С. 125–142. doi: 10.1159/000507055

[3] Tsang JYS, Tse GM. Molecular classification of breast cancer. Adv Anat Pathol. 2020; 27(1):27–35. doi: 10.1097/PAP.0000000000000232

[4] Tsang J.Y.S., Tse G.M. Molecular classification of breast cancer // Adv Anat Pathol. 2020. Vol. 27, N 1. P. 27–35. doi: 10.1097/PAP.0000000000000232

[5] Mei P, Freitag CE, Wei L, et al. High tumor mutation burden is associated with DNA damage repair gene mutation in breast carcinomas. Diagn Pathol. 2020;15(1):50. doi: 10.1186/s13000-020-00971-7

[6] Mei P., Freitag C.E., Wei L., et al. High tumor mutation burden is associated with DNA damage repair gene mutation in breast carcinomas // Diagn Pathol. 2020. Vol. 15, N 1. P. 50. doi: 10.1186/s13000-020-00971-7

[7] Segovia-Mendoza M, Morales-Montor J. Immune tumor microenvironment in breast cancer and the participation of estrogen and its receptors in cancer physiopathology. Front Immunol. 2019;10:348. doi: 10.3389/fimmu.2019.00348

[8] Segovia-Mendoza M., Morales-Montor J. Immune tumor microenvironment in breast cancer and the participation of estrogen and its receptors in cancer physiopathology // Front Immunol. 2019. Vol. 10. P. 348. doi: 10.3389/fimmu.2019.00348

[9] Ogiya R, Niikura N, Kumaki N, et al. Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer patients. Cancer Sci. 2016;107(12):1730–1735. doi: 10.1111/cas.13101

[10] Ogiya R., Niikura N., Kumaki N., et al. Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer patients // Cancer Sci. 2016. Vol. 107, N 12. P. 1730–1735. doi: 10.1111/cas.13101

[11] Sobottka B, Pestalozzi B, Fink D, et al. Similar lymphocytic infiltration pattern in primary breast cancer and their corresponding distant metastases. Oncoimmunology. 2016;5(6):e1153208. doi: 10.1080/2162402X.2016.1153208

[12] Sobottka B., Pestalozzi B., Fink D., et al. Similar lymphocytic infiltration pattern in primary breast cancer and their corresponding distant metastases // Oncoimmunology. 2016. Vol. 5, N 6. P. e1153208. doi: 10.1080/2162402X.2016.1153208

[13] Egelston CA, Guo W, Tan J, et al. Tumor-infiltrating exhausted CD8+ T cells dictate reduced survival in premenopausal estrogen receptor–positive breast cancer. JCI Insight. 2022;7(3):e153963. doi: 10.1172/jci.insight.153963

[14] Egelston C.A., Guo W., Tan J., et al. Tumor-infiltrating exhausted CD8+ T cells dictate reduced survival in premenopausal estrogen receptor–positive breast cancer // JCI Insight. 2022. Vol. 7, N 3. P. e153963. doi: 10.1172/jci.insight.153963

[15] Oshi M, Asaoka M, Tokumaru Y, et al. CD8 T cell score as a prognostic biomarker for triple negative breast cancer. Int J Mol Sci. 2020;21(18):6968. doi: 10.3390/ijms21186968

[16] Oshi M., Asaoka M., Tokumaru Y., et al. CD8 T cell score as a prognostic biomarker for triple negative breast cancer // Int J Mol Sci. 2020. Vol. 21, N 18. P. 6968. doi: 10.3390/ijms21186968

[17] Sobral-Leite M, Salomon I, Opdam M, et al. Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes. Breast Cancer Res. 2019;21(1):90. doi: 10.1186/s13058-019-1176-2

[18] Sobral-Leite M., Salomon I., Opdam M., et al. Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes // Breast Cancer Res. 2019. Vol. 21, N 1. P. 90. doi: 10.1186/s13058-019-1176-2

[19] Glajcar A, Szpor J, Hodorowicz-Zaniewska D, et al. The composition of T cell infiltrates varies in primary invasive breast cancer of different molecular subtypes as well as according to tumor size and nodal status. Virchows Arch. 2019;475(1):13–23. doi: 10.1007/s00428-019-02568-y

[20] Glajcar A., Szpor J., Hodorowicz-Zaniewska D., et al. The composition of T cell infiltrates varies in primary invasive breast cancer of different molecular subtypes as well as according to tumor size and nodal status // Virchows Arch. 2019. Vol. 475, N 1. P. 13–23. doi: 10.1007/s00428-019-02568-y

[21] Wang S, Yao Y, Yao M, et al. Interleukin-22 promotes triple negative breast cancer cells migration and paclitaxel resistance through JAK-STAT3/MAPKs/AKT signaling pathways. Biochem Biophys Res Commun. 2018;503(3):1605–1609. doi: 10.1016/j.bbrc.2018.07.088

[22] Wang S., Yao Y., Yao M., et al. Interleukin-22 promotes triple negative breast cancer cells migration and paclitaxel resistance through JAK-STAT3/MAPKs/AKT signaling pathways // Biochem Biophys Res Commun. 2018. Vol. 503, N 3. P. 1605–1609. doi: 10.1016/j.bbrc.2018.07.088

[23] Karpisheh V, Ahmadi M, Abbaszadeh-Goudarzi K, et al. The role of Th17 cells in the pathogenesis and treatment of breast cancer. Cancer Cell Int. 2022;22(1):108. doi: 10.1186/s12935-022-02528-8

[24] Karpisheh V., Ahmadi M., Abbaszadeh-Goudarzi K., et al. The role of Th17 cells in the pathogenesis and treatment of breast cancer // Cancer Cell Int. 2022. Vol. 22, N 1. P. 108. doi: 10.1186/s12935-022-02528-8

[25] Kos K, de Visser KE. The multifaceted role of regulatory t cells in breast cancer. Annu Rev Cancer Biol. 2021;5:291–310. doi: 10.1146/annurev-cancerbio-042920-104912

[26] Kos K., de Visser K.E. The multifaceted role of regulatory t cells in breast cancer // Annu Rev Cancer Biol. 2021. Vol. 5. P. 291–310. doi: 10.1146/annurev-cancerbio-042920-104912

[27] Peng GL, Li L, Guo YW, et al. CD8+ cytotoxic and FoxP3+ regulatory T lymphocytes serve as prognostic factors in breast cancer. Am J Transl Res. 2019;11(8):5039–5053.

[28] Peng G.L., Li L., Guo Y.W., et al. CD8+ cytotoxic and FoxP3+ regulatory T lymphocytes serve as prognostic factors in breast cancer // Am J Transl Res. 2019. Vol. 11, N 8. P. 5039–5053.

[29] Solis-Castillo LA, Garcia-Romo GS, Diaz-Rodriguez A, et al. Tumor-infiltrating regulatory T cells, CD8/Treg ratio, and cancer stem cells are correlated with lymph node metastasis in patients with early breast cancer. Breast Cancer. 2020;27(5):837–849. doi: 10.1007/s12282-020-01079-y

[30] Solis-Castillo L.A., Garcia-Romo G.S., Diaz-Rodriguez A., et al. Tumor-infiltrating regulatory T cells, CD8/Treg ratio, and cancer stem cells are correlated with lymph node metastasis in patients with early breast cancer // Breast Cancer. 2020. Vol. 27, N 5. P. 837–849. doi: 10.1007/s12282-020-01079-y

[31] Laumont CM, Banville AC, Gilardi M, et al. Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities. Nat Rev Cancer. 2022;22(7):414–430. doi: 10.1038/s41568-022-00466-1

[32] Laumont C.M., Banville A.C., Gilardi M., et al. Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities // Nat Rev Cancer. 2022. Vol. 22, N 7. P. 414–430. doi: 10.1038/s41568-022-00466-1

[33] Hu Q, Hong Y, Qi P, et al. Atlas of breast cancer infiltrated B-lymphocytes revealed by paired single-cell RNA-sequencing and antigen receptor profiling. Nat Commun. 2021;12(1):2186. doi: 10.1038/s41467-021-22300-2

[34] Hu Q., Hong Y., Qi P., et al. Atlas of breast cancer infiltrated B-lymphocytes revealed by paired single-cell RNA-sequencing and antigen receptor profiling // Nat Commun. 2021. Vol. 12, N 1. P. 2186. doi: 10.1038/s41467-021-22300-2

[35] Noël G, Fontsa ML, Garaud S, et al. Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity. Clin Invest. 2021;131(19):e139905. doi: 10.1172/JCI139905

[36] Noël G., Fontsa M.L., Garaud S., et al. Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity // J Clin Invest. 2021. Vol. 131, N 19. P. e139905. doi: 10.1172/JCI139905

[37] Mehta AK, Kadel S, Townsend MG, et al. Macrophage biology and mechanisms of immune suppression in breast cancer. Front Immunol. 2021;12:643771. doi: 10.3389/fimmu.2021.643771

[38] Mehta A.K., Kadel S., Townsend M.G., et al. Macrophage biology and mechanisms of immune suppression in breast cancer // Front Immunol. 2021. Vol. 12. P. 643771. doi: 10.3389/fimmu.2021.643771

[39] Castellaro AM, Rodriguez-Baili MC, Di Tada CE, Gil GA. Tumor-associated macrophages induce endocrine therapy resistance in ER+ breast cancer cells. Cancers (Basel). 2019;11(2):189. doi: 10.3390/cancers11020189

[40] Castellaro A.M., Rodriguez-Baili M.C., Di Tada C.E., Gil G.A. Tumor-associated macrophages induce endocrine therapy resistance in ER+ breast cancer cells // Cancers (Basel). 2019. Vol. 11, N 2. P. 189. doi: 10.3390/cancers11020189

[41] Kuroda H, Jamiyan T, Yamaguchi R, et al. Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes. Clin Transl Oncol. 2021;23(12):2513–2525. doi: 10.1007/s12094-021-02652-3

[42] Kuroda H., Jamiyan T., Yamaguchi R., et al. Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes // Clin Transl Oncol. 2021. Vol. 23, N 12. P. 2513–2525. doi: 10.1007/s12094-021-02652-3

[43] Minns D, Smith KJ, Hardisty G, et al. The outcome of neutrophil-t cell contact differs depending on activation status of both cell types. Front Immunol. 2021;12:633486. doi: 10.3389/fimmu.2021.633486

[44] Minns D., Smith K.J., Hardisty G., et al. The outcome of neutrophil-t cell contact differs depending on activation status of both cell types // Front Immunol. 2021. Vol. 12. P. 633486. doi: 10.3389/fimmu.2021.633486

[45] Ohms M, Möller S, Laskay T. An attempt to polarize human neutrophils toward n1 and n2 phenotypes in vitro. Front Immunol. 2020;11:532. doi: 10.3389/fimmu.2020.00532

[46] Ohms M., Möller S., Laskay T. An attempt to polarize human neutrophils toward N1 and N2 phenotypes in vitro // Front Immunol. 2020. Vol. 11. P. 532. doi: 10.3389/fimmu.2020.00532

[47] Geng SK, Fu SM, Ma SH, et al. Tumor infiltrating neutrophil might play a major role in predicting the clinical outcome of breast cancer patients treated with neoadjuvant chemotherapy. BMC Cancer. 2021;21(1):68. doi: 10.1186/s12885-021-07789-6

[48] Geng S.K., Fu S.M., Ma S.H., et al. Tumor infiltrating neutrophil might play a major role in predicting the clinical outcome of breast cancer patients treated with neoadjuvant chemotherapy // BMC Cancer. 2021. Vol. 21, N 1. P. 68. doi: 10.1186/s12885-021-07789-6

[49] Hu G, Xu F, Zhong K, et al. Activated tumor-infiltrating fibroblasts predict worse prognosis in breast cancer patients. J Cancer. 2018;9(20):3736–3742. doi: 10.7150/jca.28054

[50] Hu G., Xu F., Zhong K., et al. Activated tumor-infiltrating fibroblasts predict worse prognosis in breast cancer patients // J Cancer. 2018. Vol. 9, N 20. P. 3736–3742. doi: 10.7150/jca.28054

[51] Costa A, Kieffer Y, Scholer-Dahirel A, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33(3):463–479.e10. doi: 10.1016/j.ccell.2018.01.011

[52] Costa A., Kieffer Y., Scholer-Dahirel A., et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer // Cancer Cell. 2018. Vol. 33, N 3. P. 463–479.e10. doi: 10.1016/j.ccell.2018.01.011

[53] Kuczek DE, Larsen AMH, Thorseth ML, et al. Collagen density regulates the activity of tumor-infiltrating T cells. J Immunother Cancer. 2019;7(1):68. doi: 10.1186/s40425-019-0556-6

[54] Kuczek D.E., Larsen A.M.H., Thorseth M.L., et al. Collagen density regulates the activity of tumor-infiltrating T cells // J Immunother Cancer. 2019. Vol. 7, N 1. P. 68. doi: 10.1186/s40425-019-0556-6

[55] Elaraby E, Malek AI, Abdullah HW, et al. Natural killer cell dysfunction in obese patients with breast cancer: a review of a triad and its implications. J Immunol Res. 2021;2021:9972927. doi: 10.1155/2021/9972927

[56] Elaraby E., Malek A.I., Abdullah H.W., et al. Natural killer cell dysfunction in obese patients with breast cancer: a review of a triad and its implications // J Immunol Res. 2021. Vol. 2021. P. 9972927. doi: 10.1155/2021/9972927

[57] Bouzidi L, Triki H, Charfi S, et al. Prognostic value of natural killer cells besides tumor-infiltrating lymphocytes in breast cancer tissues. Clin Breast Cancer. 2021;21(6):e738–e747. doi: 10.1016/j.clbc.2021.02.003

[58] Bouzidi L., Triki H., Charfi S., et al. Prognostic value of natural killer cells besides tumor-infiltrating lymphocytes in breast cancer tissues // Clin Breast Cancer. 2021. Vol. 21, N 6. P. e738–e747. doi: 10.1016/j.clbc.2021.02.003

[59] O’Meara T, Marczyk M, Qing T, et al. Immunological differences between immune-rich estrogen receptor-positive and immune-rich triple-negative breast cancers. JCO Precis Oncol. 2020;4:PO.19.00350. doi: 10.1200/PO.19.00350

[60] O’Meara T., Marczyk M., Qing T., et al. Immunological differences between immune-rich estrogen receptor-positive and immune-rich triple-negative breast cancers // JCO Precis Oncol. 2020. Vol. 4. P. PO.19.00350. doi: 10.1200/PO.19.00350.

[61] Chan IS, Knútsdóttir H, Ramakrishnan G, et al. Cancer cells educate natural killer cells to a metastasis-promoting cell state. J Cell Biol. 2020;219(9):e202001134. doi: 10.1083/jcb.202001134

[62] Chan I.S., Knútsdóttir H., Ramakrishnan G., et al. Cancer cells educate natural killer cells to a metastasis-promoting cell state // J Cell Biol. 2020. Vol. 219, N 9. P. e202001134. doi: 10.1083/jcb.202001134

[63] Al Absi A, Wurzer H, Guerin C, et al. Actin cytoskeleton remodeling drives breast cancer cell escape from natural killer–mediated cytotoxicity. Cancer Res. 2018;78(19):5631–5643. doi: 10.1158/0008-5472.CAN-18-0441

[64] Al Absi A., Wurzer H., Guerin C., et al. Actin cytoskeleton remodeling drives breast cancer cell escape from natural killer–mediated cytotoxicity // Cancer Res. 2018. Vol. 78, N 19. P. 5631–5643. doi: 10.1158/0008-5472.CAN-18-0441

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