Temporal Changes in Immune Responses within the Tumor Microenvironment in the 4T1.2-HER2 Mammary Tumor Model Article Swipe

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YOU? · · 2021 · Open Access · · DOI: https://doi.org/10.21203/rs.3.rs-180530/v1

Background: The murine 4T1.2 triple-negative breast cancer model is widely used, but is poorly immunogenic with no defined tumor-associated antigens. A modified 4T1.2 model has been developed that stably expresses a surrogate tumor antigen, human epidermal growth factor receptor-2 (HER2). The goal of the current study was to characterize host immune responses in the 4T1.2-HER2 tumor model, focusing on the tumor microenvironment (TME) during the early stage of tumor development. Methods: Female BALB/c mice were orthotopically inoculated with 4T1.2-HER2 tumor cells and sacrificed at day (D) 6, 9, 12, 15 and 18 post tumor inoculation. The phenotype and function of tumor-infiltrating immune cells were assessed. Results: 4T1.2 and 4T1.2-HER2 tumor cells had similar proliferation rates in vitro . In contrast to the rapid progression of the parental 4T1.2 model, the 4T1.2-HER2 model demonstrated initial tumor growth followed by spontaneous tumor regression by D18 post tumor inoculation, which was not observed in scid mice. Following tumor regression, mice demonstrated either a second phase of tumor outgrowth or complete tumor rejection. Within the TME, the percentage of T cells was reduced at D9 and increased during tumor regression through D18 (p<0.05), whereas the percentage of myeloid-derived suppressor cells (MDSCs) increased during the initial tumor growth and was reduced by D18 (p<0.01). There was a stepwise increase in the percentage of IFNg + , IL-2 + and perforin + T cells and NK cells peaking at D12-15. Furthermore, tumor regression occurred concurrently with HER2-specific IFNg production from tumor-infiltrating immune cells at D12 and D15 (p<0.05). During the second phase of 4T1.2-HER2 tumor growth, tumor volume was negatively correlated with immune infiltration (r=0.662, p=0.052). Conclusions: These results suggest that the integration of a surrogate tumor antigen, human HER2, into the clinically relevant, yet poorly immunogenic 4T1.2 breast cancer model enhanced its immunogenicity and induced HER2-specific immune responses.

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Mammary tumor Tumor microenvironment Immune system Breast tumor Immune escape Biology Cancer research Medicine Cancer Immunology Breast cancer Internal medicine

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Type: preprint
Language: en
Landing Page: https://doi.org/10.21203/rs.3.rs-180530/v1
PDF: https://www.researchsquare.com/article/rs-180530/latest.pdf
OA Status: green
Cited By: 1
References: 39
Related Works: 10
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DOI: https://doi.org/10.21203/rs.3.rs-180530/v1

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Title: Temporal Changes in Immune Responses within the Tumor Microenvironment in the 4T1.2-HER2 Mammary Tumor Model

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Type: preprint

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Language: en

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Publication year: 2021

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Publication date: 2021-02-09

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Authors: Yitong Xu, Connie J. Rogers

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Landing page: https://doi.org/10.21203/rs.3.rs-180530/v1

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Concepts: Mammary tumor, Tumor microenvironment, Immune system, Breast tumor, Immune escape, Biology, Cancer research, Medicine, Cancer, Immunology, Breast cancer, Internal medicine

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Cited by: 1

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abstract_inverted_index.stepwise	213
abstract_inverted_index.(r=0.662,	269
abstract_inverted_index.Following	154
abstract_inverted_index.antigens.	20
abstract_inverted_index.assessed.	105
abstract_inverted_index.developed	27
abstract_inverted_index.epidermal	36
abstract_inverted_index.expresses	30
abstract_inverted_index.increased	183, 198
abstract_inverted_index.outgrowth	165
abstract_inverted_index.p=0.052).	270
abstract_inverted_index.phenotype	97
abstract_inverted_index.relevant,	288
abstract_inverted_index.responses	52
abstract_inverted_index.surrogate	32, 280
abstract_inverted_index.4T1.2-HER2	55, 79, 109, 131, 258
abstract_inverted_index.clinically	287
abstract_inverted_index.correlated	265
abstract_inverted_index.inoculated	77
abstract_inverted_index.negatively	264
abstract_inverted_index.percentage	174, 192, 217
abstract_inverted_index.production	243
abstract_inverted_index.receptor-2	39
abstract_inverted_index.regression	141, 186, 237
abstract_inverted_index.rejection.	169
abstract_inverted_index.responses.	303
abstract_inverted_index.sacrificed	83
abstract_inverted_index.suppressor	195
abstract_inverted_index.Background:	1
abstract_inverted_index.immunogenic	15, 291
abstract_inverted_index.integration	277
abstract_inverted_index.progression	124
abstract_inverted_index.regression,	156
abstract_inverted_index.spontaneous	139
abstract_inverted_index.(p<0.01).	209
abstract_inverted_index.(p<0.05),	189
abstract_inverted_index.(p<0.05).	252
abstract_inverted_index.Conclusions:	271
abstract_inverted_index.Furthermore,	235
abstract_inverted_index.characterize	49
abstract_inverted_index.concurrently	239
abstract_inverted_index.demonstrated	133, 158
abstract_inverted_index.development.	70
abstract_inverted_index.infiltration	268
abstract_inverted_index.inoculation,	146
abstract_inverted_index.inoculation.	95
abstract_inverted_index.HER2-specific	241, 301
abstract_inverted_index.proliferation	114
abstract_inverted_index.immunogenicity	298
abstract_inverted_index.orthotopically	76
abstract_inverted_index.myeloid-derived	194
abstract_inverted_index.triple-negative	5
abstract_inverted_index.microenvironment	62
abstract_inverted_index.tumor-associated	19
abstract_inverted_index.tumor-infiltrating	101, 245
cited_by_percentile_year.max	94
cited_by_percentile_year.min	89
countries_distinct_count	1
institutions_distinct_count	2
sustainable_development_goals[0].id	https://metadata.un.org/sdg/3
sustainable_development_goals[0].score	0.7300000190734863
sustainable_development_goals[0].display_name	Good health and well-being
citation_normalized_percentile.value	0.43119598
citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	False