T Cells Resistant to PD-1 Blockade Promote Generation and Maintenance of Aggressive Cancer Stem Cells Article Swipe

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Mohona Chakravarti , Sukanya Dhar , Saurav Bera , Abhipsa Sinha , Kamalika Roy , Anirban Sarkar , Shayani Dasgupta , Avishek Bhuniya , Akata Saha , Juhina Das , Saptak Banerjee , Manisha Vernekar , Chiranjib Pal , Neyaz Alam , Dipak Datta , Rathindranath Baral , Anamika Bose ·

YOU? · · 2023 · Open Access · · DOI: https://doi.org/10.1158/0008-5472.c.6653433

Heterogeneity within the tumor-infiltrating lymphocytes (TIL) population limits immunotherapeutic efficacy against cancer. Between two subpopulations of exhausted CD8⁺ TILs (progenitor-exhausted; T_PEX, terminally exhausted; T_TEX), T_TEX cells remain unresponsive to anti–programmed cell death protein 1(PD-1) therapy. Deciphering whether and how PD-1–resistant T_TEX cells engage in tumor promotion could improve the response to immunotherapy. Here, we report that T_TEX cells actively participate in tumor progression by modulating cancer stem cells (CSC). T_TEX cells strongly correlated with elevated CSC frequency in poorly immune-infiltrated (CD8⁺ TIL low) advanced human breast and ovarian carcinomas. T_TEX directly upregulated CSC frequency in vitro, which was not affected by anti–PD-1 treatment. The T_TEX-influenced CSCs were highly clonogenic and exhibited a multidrug-resistant phenotype, overexpressing drug efflux pumps like ABCC1 and ABCB1. These CSCs were highly invasive, displaying increased invadopodia development and elevated cofilin, CXCR4, and matrix metalloproteinase 7 (MMP7) expression. The invasive properties along with epithelial–mesenchymal plasticity of T_TEX-educated CSCs increased metastasis in vivo. T_TEX increased cell surface levels and activation of VEGFR2 in CSCs, and silencing or inhibition of VEGFR2 reversed the CSC-stimulatory effects of T_TEX. LAMP3 and NRP1 on the surface of T_TEX stimulated VEGFR2 in CSCs to promote aggressiveness. Cumulatively, these findings suggest that screening patients with carcinoma for both CD8⁺ TILs and T_TEX frequency prior to anti–PD-1 therapy could improve patient outcomes. In addition, targeting the LAMP3/NRP1–VEGFR2 axis could be a therapeutic strategy in advanced patients with carcinoma with limited CD8⁺ T-cell infiltration and high T_TEX frequency.Significance:Cross-talk with T_TEX CD8⁺ T cells mediated by the VEGFR2 axis induces aggressive properties in cancer stem cells to promote tumor progression.

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Blockade Cancer research Cytotoxic T cell CD8 Stem cell Cell biology Biology Chemistry Biochemistry Immunology Immune system In vitro Receptor

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1158/0008-5472.c.6653433
OA Status: gold
Related Works: 10
OpenAlex ID: https://openalex.org/W4377020892

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DOI: https://doi.org/10.1158/0008-5472.c.6653433

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Title: Data from Terminally Exhausted CD8<sup>+</sup> T Cells Resistant to PD-1 Blockade Promote Generation and Maintenance of Aggressive Cancer Stem Cells

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Type: preprint

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Language: en

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Publication year: 2023

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Publication date: 2023-05-18

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Authors: Mohona Chakravarti, Sukanya Dhar, Saurav Bera, Abhipsa Sinha, Kamalika Roy, Anirban Sarkar, Shayani Dasgupta, Avishek Bhuniya, Akata Saha, Juhina Das, Saptak Banerjee, Manisha Vernekar, Chiranjib Pal, Neyaz Alam, Dipak Datta, Rathindranath Baral, Anamika Bose

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Landing page: https://doi.org/10.1158/0008-5472.c.6653433

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Concepts: Blockade, Cancer research, Cytotoxic T cell, CD8, Stem cell, Cell biology, Biology, Chemistry, Biochemistry, Immunology, Immune system, In vitro, Receptor

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abstract_inverted_index.frequency	76, 93, 208
abstract_inverted_index.increased	128, 151, 156
abstract_inverted_index.invasive,	126
abstract_inverted_index.outcomes.	216
abstract_inverted_index.promotion	45
abstract_inverted_index.screening	198
abstract_inverted_index.silencing	167
abstract_inverted_index.targeting	219
abstract_inverted_index.activation	161
abstract_inverted_index.aggressive	253
abstract_inverted_index.clonogenic	108
abstract_inverted_index.correlated	72
abstract_inverted_index.displaying	127
abstract_inverted_index.exhausted;	22
abstract_inverted_index.inhibition	169
abstract_inverted_index.metastasis	152
abstract_inverted_index.modulating	64
abstract_inverted_index.phenotype,	113
abstract_inverted_index.plasticity	147
abstract_inverted_index.population	6
abstract_inverted_index.properties	143, 254
abstract_inverted_index.stimulated	186
abstract_inverted_index.terminally	21
abstract_inverted_index.treatment.	102
abstract_inverted_index.<i>in	94, 153
abstract_inverted_index.Deciphering	35
abstract_inverted_index.anti–PD-1	101, 211
abstract_inverted_index.carcinomas.	88
abstract_inverted_index.development	130
abstract_inverted_index.expression.	140
abstract_inverted_index.invadopodia	129
abstract_inverted_index.lymphocytes	4
abstract_inverted_index.participate	59
abstract_inverted_index.progression	62
abstract_inverted_index.therapeutic	226
abstract_inverted_index.upregulated	91
abstract_inverted_index.infiltration	237
abstract_inverted_index.unresponsive	27
abstract_inverted_index.Cumulatively,	193
abstract_inverted_index.immunotherapy.	51
abstract_inverted_index.overexpressing	114
abstract_inverted_index.subpopulations	14
abstract_inverted_index.CSC-stimulatory	174
abstract_inverted_index.aggressiveness.	192
abstract_inverted_index.vivo</i>.	154
abstract_inverted_index.PD-1–resistant	39
abstract_inverted_index.vitro</i>,	95
abstract_inverted_index.anti–programmed	29
abstract_inverted_index.immunotherapeutic	8
abstract_inverted_index.metalloproteinase	137
abstract_inverted_index.immune-infiltrated	79
abstract_inverted_index.tumor-infiltrating	3
abstract_inverted_index.LAMP3/NRP1–VEGFR2	221
abstract_inverted_index.multidrug-resistant	112
abstract_inverted_index.(progenitor-exhausted;	19
abstract_inverted_index.epithelial–mesenchymal	146
abstract_inverted_index.CD8<sup>+</sup>	17, 204, 235, 244
abstract_inverted_index.T<sub>TEX</sub>	24, 40, 56, 69, 89, 155, 185, 207, 240, 243
abstract_inverted_index.(CD8<sup>+</sup>	80
abstract_inverted_index.T<sub>PEX</sub>,	20
abstract_inverted_index.T<sub>TEX</sub>.	177
abstract_inverted_index.T<sub>TEX</sub>),	23
abstract_inverted_index.progression.</p></div>	262
abstract_inverted_index.T<sub>TEX</sub>-educated	149
abstract_inverted_index.T<sub>TEX</sub>-influenced	104
abstract_inverted_index.<div>Abstract<p>Heterogeneity	0
abstract_inverted_index.frequency.</p>Significance:<p>Cross-talk	241
cited_by_percentile_year
countries_distinct_count	0
institutions_distinct_count	17
sustainable_development_goals[0].id	https://metadata.un.org/sdg/3
sustainable_development_goals[0].score	0.8299999833106995
sustainable_development_goals[0].display_name	Good health and well-being
citation_normalized_percentile.value	0.35462462
citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	False