Association of HIV Status With Local Immune Response to Anal Squamous Cell Carcinoma: Implications for Immunotherapy.
OBJECTIVE
The programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway play an important immunosuppressive role in cancer and chronic viral infection, and have been effectively targeted in cancer therapy. Anal squamous cell carcinoma (SCC) is associated with both human papillomavirus and HIV infection. To date, patients with HIV have been excluded from most trials of immune checkpoint blocking agents, such as anti-PD-1 and anti-PD-L1, because it was assumed that their antitumor immunity was compromised compared with immunocompetent patients.


OBJECTIVE
To compare the local tumor immune microenvironment (TME) in anal SCCs from HIV-positive and HIV-negative patients.


METHODS
Anal SCC tumor specimens derived from the AIDS and Cancer Specimen Resource (National Cancer Institute) and Johns Hopkins Hospital included specimens. Tumors were subjected to immunohistochemical analysis for immune checkpoints (PD-L1, PD-1, LAG-3) and immune cell (IC) subsets (CD3, CD4, CD8, CD68). Expression profiling for immune-related genes was performed on select HIV-positive and HIV-negative cases in PD-L1+ tumor areas associated with ICs.


METHODS
Programmed death-ligand 1 expression on tumor cells and ICs, PD-L1 patterns (adaptive vs constitutive), degree of IC infiltration, quantified densities of IC subsets, and gene expression profiles in anal SCCs from HIV-positive vs HIV-negative patients.


RESULTS
Approximately half of 40 tumor specimens from 23 HIV-positive and 17 HIV-negative patients (29 men and 11 women; mean [SD] age, 51 [9.9] years) demonstrated tumor cell PD-L1 expression, regardless of HIV status. Median IC densities were not significantly decreased in HIV-associated tumors for any cellular subset studied. Both adaptive (IC-associated) and constitutive PD-L1 expression patterns were observed. Immune cell PD-L1 expression correlated with increasing intensity of IC infiltration (r = 0.52; 95% CI, 0.26-0.78; P < .001) and with CD8+ T-cell density (r = 0.35; 95% CI, 0.11-0.59; P = .03). Gene expression profiling revealed comparable levels of IFNG in the TME of both HIV-positive and HIV-negative patients. A significant increase in IL18 expression levels was observed in HIV-associated anal SCCs (fold change, 12.69; P < .001).


CONCLUSIONS
HIV status does not correlate with the degree or composition of IC infiltration or PD-L1 expression in anal SCC. These findings demonstrate an immune-reactive TME in anal SCCs from HIV-positive patients and support clinical investigations of PD-1/PD-L1 checkpoint blockade in anal SCC, irrespective of patient HIV status.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
Elizabeth L
EL
Yanik
Department of Dermatology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Genevieve J
GJ
Kaunitz
Department of Pathology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Tricia R
TR
Cottrell
Department of Dermatology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Farah
F
Succaria
Department of Surgery, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Tracee L
TL
McMiller
Department of Oncology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Maria L
ML
Ascierto
Department of Dermatology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland3Department of Pathology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Jessica
J
Esandrio
Department of Dermatology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Haiying
H
Xu
Department of Dermatology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Aleksandra
A
Ogurtsova
Department of Pathology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland6Department of Pathology, University of Colorado School of Medicine, Aurora.
Toby
T
Cornish
Department of Oncology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Evan J
EJ
Lipson
Department of Surgery, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Suzanne L
SL
Topalian
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
Eric A
EA
Engels
Department of Dermatology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland3Department of Pathology, Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland.
Janis M
JM
Taube
D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D001005:Anus Neoplasms / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D060890:B7-H1 Antigen / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D016022:Case-Control Studies; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D020382:Interleukin-18 / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D060890:B7-H1 Antigen; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D020382:Interleukin-18; D000093322:Lymphocyte Activation Gene 3 Protein; C423236:CD274 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C000720326:Lag3 protein, human