Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males

Mariam Saad; Sandra J Lee; Aik Choon Tan; Issam M El Naqa; F Stephen Hodi; Lisa H Butterfield; William A LaFramboise; Walter Storkus; Arivarasan D Karunamurthy; Jose Conejo-Garcia; Patrick Hwu; Howard Streicher; Vernon K Sondak; John M Kirkwood; Ahmad A Tarhini

doi:10.1186/s12967-022-03450-3

Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males

J Transl Med. 2022 Jun 3;20(1):253. doi: 10.1186/s12967-022-03450-3.

Authors

Mariam Saad¹, Sandra J Lee², Aik Choon Tan³, Issam M El Naqa⁴, F Stephen Hodi⁵, Lisa H Butterfield⁶, William A LaFramboise⁷, Walter Storkus⁸, Arivarasan D Karunamurthy⁸, Jose Conejo-Garcia⁹, Patrick Hwu¹⁰, Howard Streicher¹¹, Vernon K Sondak¹², John M Kirkwood^{8

13}, Ahmad A Tarhini¹⁴

Affiliations

¹ Departments of Cutaneous Oncology and Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA, 10920 McKinley Dr.
² Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
³ Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA, Florida.
⁴ Department of Machine Learning, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
⁵ Dana Farber Cancer Institute, Boston, MA, USA.
⁶ Univ. California San Francisco and The Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
⁷ Allegheny Health Network Cancer Institute, Pathology, Pittsburgh, PA, USA.
⁸ University of Pittsburgh School of Medicine (UPSOM), Pittsburgh, PA, USA.
⁹ Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Florida, Tampa, USA.
¹⁰ Administration, Cutaneous Oncology, Immunology, H. Lee Moffitt Cancer Center and Research Institute, Florida, Tampa, USA.
¹¹ National Cancer Institute, Rockville, MD, USA.
¹² Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Florida, Tampa, USA.
¹³ UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁴ Departments of Cutaneous Oncology and Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA, 10920 McKinley Dr.. Ahmad.Tarhini@moffitt.org.

Abstract

Background: We hypothesized that a gender difference in clinical response may exist to adjuvant CTLA4 blockade with ipilimumab versus high-dose IFNα (HDI). We investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME).

Patients and methods: This gender-based analysis was nested within the E1609 trial that tested adjuvant therapy with ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus HDI in high risk resected melanoma. We investigated gender differences in treatment efficacy with ipi3 and ipi10 versus HDI while adjusting for age, stage, ECOG performance (PS), ulceration, primary tumor status and lymph node number. Forest plots were created to compare overall survival (OS) and relapse free survival (RFS) between ipi and HDI. Gene expression profiling (GEP) was performed on tumors of 718 (454 male, 264 female) patients. Similarly, serum and peripheral blood mononuclear cells (PBMC) samples were tested for soluble and cellular biomarkers (N = 321 patients; 109 female and 212 male).

Results: The subgroups of female, stage IIIC, PS = 1, ulcerated primary, in-transit metastasis demonstrated significant improvement in RFS and/or OS with ipi3 versus HDI. Female gender was significant for both OS and RFS and was further explored. In the RFS comparison, a multivariate Cox regression model including significant variables indicated a significant interaction between gender and treatment (P = 0.024). In peripheral blood, percentages of CD3+ T cells (P = 0.024) and CD3+ CD4+ helper T cells (P = 0.0001) were higher in females compared to males. Trends toward higher circulating levels of IL1β (P = 0.07) and IL6 (P = 0.06) were also found in females. Males had higher percentages of monocytes (P = 0.03) with trends toward higher percentages of regulatory T cells (T-reg). Tumor GEP analysis supported enhanced infiltration with immune cells including gammadelta T cells (P = 0.005), NK cells (P = 0.01), dendritic cells (P = 0.01), CD4+ T cells (P = 0.03), CD8+ T cells (P = 0.03) and T-reg (P = 0.008) in the tumors of females compared to males and a higher T-effector and IFNγ gene signature score (P = 0.0244).

Conclusion: Female gender was associated with adjuvant CTLA4 blockade clinical benefits and female patients were more likely to have evidence of type1 immune activation within the TME and the circulation. Trial registration ClinicalTrials.gov NCT01274338. Registered 11 January 2011, https://www.

Clinicaltrials: gov/ct2/show/NCT01274338.

Keywords: Adjuvant; Female; Interferon; Ipilimumab; Male; Melanoma.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adjuvants, Immunologic / therapeutic use
CTLA-4 Antigen / genetics
Female
Humans
Interferon-alpha
Ipilimumab / therapeutic use
Leukocytes, Mononuclear / pathology
Male
Melanoma* / drug therapy
Melanoma* / genetics
Neoplasm Recurrence, Local / pathology
Neoplasm Staging
Skin Neoplasms* / drug therapy
Skin Neoplasms* / genetics
Tumor Microenvironment

Substances

Adjuvants, Immunologic
CTLA-4 Antigen
CTLA4 protein, human
Interferon-alpha
Ipilimumab

Associated data

ClinicalTrials.gov/NCT01274338

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding