PMID- 30777877
OWN - NLM
STAT- In-Data-Review
LR  - 20190604
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 25
IP  - 11
DP  - 2019 Jun 1
TI  - Prevalence and Cellular Distribution of Novel Immune Checkpoint Targets Across
      Longitudinal Specimens in Treatment-naive Melanoma Patients: Implications for
      Clinical Trials.
PG  - 3247-3258
LID - 10.1158/1078-0432.CCR-18-4011 [doi]
AB  - PURPOSE: Immunotherapies targeting costimulating and coinhibitory checkpoint
      receptors beyond PD-1 and CTLA-4 have entered clinical trials. Little is known
      about the relative abundance, coexpression, and immune cells enriched for each
      specific drug target, limiting understanding of the biological basis of potential
      treatment outcomes and development of predictive biomarkers for personalized
      immunotherapy. We sought to assess the abundance of checkpoint receptors during
      melanoma disease progression and identify immune cells enriched for
      them.Experimental Design: Multiplex immunofluorescence staining for immune
      checkpoint receptors (ICOS, GITR, OX40, PD-1, TIM-3, VISTA) was performed on 96
      melanoma biopsies from 41 treatment-naive patients, including patient-matched
      primary tumors, nodal metastases, and distant metastases. Mass cytometry was
      conducted on tumor dissociates from 18 treatment-naive melanoma metastases to
      explore immune subsets enriched for checkpoint receptors. RESULTS: A small subset
      of tumor-infiltrating leukocytes expressed checkpoint receptors at any stage of
      melanoma disease. GITR and OX40 were the least abundant checkpoint receptors,
      with <1% of intratumoral T cells expressing either marker. ICOS, PD-1, TIM-3, and
      VISTA were most abundant, with TIM-3 and VISTA mostly expressed on non-T cells,
      and TIM-3 enriched on dendritic cells. Tumor-resident T cells
      (CD69(+)/CD103(+)/CD8(+)) were enriched for TIGIT (>70%) and other coinhibitory
      but not costimulatory receptors. The proportion of GITR(+) T cells decreased from
      primary melanoma (>5%) to lymph node (<1%, P = 0.04) and distant metastases (<1%,
      P = 0.0005). CONCLUSIONS: This study provides the first comprehensive assessment 
      of immune checkpoint receptor expression in any cancer and provides important
      data for rational selection of targets for trials and predictive biomarker
      development.
CI  - (c)2019 American Association for Cancer Research.
FAU - Edwards, Jarem
AU  - Edwards J
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
AD  - Sydney Medical School, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Centenary Institute, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Charles Perkins Centre, The University of Sydney, Sydney, New South Wales,
      Australia.
FAU - Tasker, Annie
AU  - Tasker A
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
AD  - Charles Perkins Centre, The University of Sydney, Sydney, New South Wales,
      Australia.
FAU - Pires da Silva, Ines
AU  - Pires da Silva I
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
FAU - Quek, Camelia
AU  - Quek C
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
AD  - Sydney Medical School, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Charles Perkins Centre, The University of Sydney, Sydney, New South Wales,
      Australia.
FAU - Batten, Marcel
AU  - Batten M
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
AD  - Charles Perkins Centre, The University of Sydney, Sydney, New South Wales,
      Australia.
FAU - Ferguson, Angela
AU  - Ferguson A
AD  - Sydney Medical School, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Centenary Institute, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Charles Perkins Centre, The University of Sydney, Sydney, New South Wales,
      Australia.
FAU - Allen, Ruth
AU  - Allen R
AD  - Centenary Institute, The University of Sydney, Sydney, New South Wales,
      Australia.
FAU - Allanson, Benjamin
AU  - Allanson B
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
AD  - Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
FAU - Saw, Robyn P M
AU  - Saw RPM
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
AD  - Sydney Medical School, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
AD  - Mater Hospital, North Sydney, Australia.
FAU - Thompson, John F
AU  - Thompson JF
AUID- ORCID: https://orcid.org/0000-0002-2816-2496
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
AD  - Sydney Medical School, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
AD  - Mater Hospital, North Sydney, Australia.
FAU - Menzies, Alexander M
AU  - Menzies AM
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
AD  - Sydney Medical School, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Mater Hospital, North Sydney, Australia.
AD  - Royal North Shore Hospital, Sydney, New South Wales Australia.
FAU - Palendira, Umaimainthan
AU  - Palendira U
AD  - Sydney Medical School, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Centenary Institute, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Charles Perkins Centre, The University of Sydney, Sydney, New South Wales,
      Australia.
FAU - Wilmott, James S
AU  - Wilmott JS
AUID- ORCID: https://orcid.org/0000-0002-6750-5244
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
AD  - Sydney Medical School, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Charles Perkins Centre, The University of Sydney, Sydney, New South Wales,
      Australia.
FAU - Long, Georgina V
AU  - Long GV
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia.
AD  - Sydney Medical School, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Charles Perkins Centre, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Mater Hospital, North Sydney, Australia.
AD  - Royal North Shore Hospital, Sydney, New South Wales Australia.
FAU - Scolyer, Richard A
AU  - Scolyer RA
AUID- ORCID: https://orcid.org/0000-0002-8991-0013
AD  - Melanoma Institute Australia, The University of Sydney, North Sydney, New South
      Wales, Australia. Richard.Scolyer@melanoma.org.au.
AD  - Sydney Medical School, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Charles Perkins Centre, The University of Sydney, Sydney, New South Wales,
      Australia.
AD  - Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
LA  - eng
PT  - Journal Article
DEP - 20190218
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for
      Cancer Research
JID - 9502500
EDAT- 2019/02/20 06:00
MHDA- 2019/02/20 06:00
CRDT- 2019/02/20 06:00
PHST- 2018/12/10 00:00 [received]
PHST- 2019/01/18 00:00 [revised]
PHST- 2019/02/13 00:00 [accepted]
PHST- 2019/02/20 06:00 [pubmed]
PHST- 2019/02/20 06:00 [medline]
PHST- 2019/02/20 06:00 [entrez]
AID - 1078-0432.CCR-18-4011 [pii]
AID - 10.1158/1078-0432.CCR-18-4011 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2019 Jun 1;25(11):3247-3258. doi: 10.1158/1078-0432.CCR-18-4011.
      Epub 2019 Feb 18.