Checkpoint inhibitors fire up different types of T cells to attack tumors

August 10, 2017, University of Texas M. D. Anderson Cancer Center
Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. Credit: NIAID

Cancer immunotherapies that block two different checkpoints on T cells launch immune attacks on cancer by expanding distinct types of T cell that infiltrate tumors, researchers from The University of Texas MD Anderson Cancer Center report in the journal Cell.

"The mechanisms these two therapies use mostly do not overlap, which provides a reason why combining them works better than either alone," said Jim Allison, Ph.D., chair and professor of Immunology at MD Anderson.

Researchers analyzed infiltrating from mouse tumor models and human melanomas treated with either anti-CTLA-4 or anti PD-1 checkpoint inhibitors. Using mass cytometry, they analyzed 33 surface markers and 10 intracellular markers to characterize infiltrating .

"The clinical successes of checkpoint blockade have gotten out ahead of our understanding of how these drugs work," Allison said. "In some ways, that's a good problem to have, but we need greater understanding of the basic science behind these drugs to use them more effectively for patients."

Uncovering the cellular mechanisms used by each type of checkpoint inhibitor opens the door to more precise understanding of how to use the drugs separately and in combination with each other and other types of therapy, Allison said.

When they analyzed immune infiltrates, lead author Spencer Wei, Ph.D., a postdoctoral fellow in Allison's lab, and colleagues found:

  • Anti-CTLA-4 treatment expands the presence of CD4 effector T cells that are positive for ICOS, an immune-stimulating protein, and that these cells were strongly associated with smaller tumors in the mice.
  • Anti-PD-1 and anti-CTLA-4 treatment greatly expands the presence of CD8 T cells, the most powerful killers in the T cell family, and they were associated with smaller tumors in the mice.
  • These PD-1 positive CD8 T cells had what scientists call an exhausted-like phenotype. They have markers of inactivity, including the presence of other immune checkpoints, but are not necessarily known to be inactive and likely still have significant functional activity.

"These cells are boosted by anti-PD-1, but they keep their exhausted phenotype, which suggests they'll shut down when the PD-1 antibody is withdrawn," Allison said. This supports the need to give the drug for long periods, and current anti-PD-1 regimens provide a year or two of treatment.

The team ran these experiments in a mouse model of melanoma known to be highly immunogenic, so vulnerable to immunotherapy, and one model that is poorly immunogenic - "more like prostate cancer than melanoma," Allison said.

The two drugs worked by expanding the same T cell infiltrates in both tumor types, so their mechanisms appear to be independent of tumor characteristics, but tumor characteristics are likely to affect the magnitude of responses.

Subsequent analyses of surgically removed human melanoma tumors showed that anti-CTLA-4 and anti-PD-1 each expanded T cell populations analogous to those found in the mouse models.

Additional research is needed to confirm and further understand these findings in larger studies, the researchers note.

Allison invented immune checkpoint blockade as a cancer therapy with his research leading to development of ipilimumab (Yervoy), and an approach of treating the immune system, rather than the tumor directly. By blocking CTLA-4, a protein on T cells that shuts down immune responses, ipilimumab unleashed the adaptive immune system to attack cancer.

Subsequently, other researchers developed inhibitors that block PD-1, a separate brake on T cells, or its main activating ligand, PD-L1, found on tumors and on normal cells.

Ipilimumab has been approved by the U.S. Food and Drug Administration alone or in combination against metastatic or inoperable melanoma. Two PD-1 inhibitors have been approved for melanoma, lung, bladder, kidney, head and neck cancers and non-Hodgkin lymphoma. Several PD-L1 inhibitors have also been approved for use in multiple types.

CTLA-4 blockade is thought to act at the initiation of , while PD1 is used by tumors to shut down an immune response that is under way by using PD-L1 to turn T cells off. About 15 to 25 percent of patients respond to these drugs, and researchers are seeking biomarkers to guide treatment and exploring new combinations to improve and expand responses.

Explore further: Immune-cell numbers predict response to combination immunotherapy in melanoma

Related Stories

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Study provides path for new immunotherapy approaches to prostate cancer

March 27, 2017
Prostate cancer, notoriously resistant to immunotherapy due to its immunologically cool nature, triggers two pathways to chill an immune attack after one immunotherapy drug fires up the immune system, researchers at The University ...

Immune analysis of on-treatment longitudinal biopsies predicts response to melanoma immunotherapy

August 10, 2016
Immune response measured in tumor biopsies during the course of early treatment predicts which melanoma patients will benefit from specific immune checkpoint blockade drugs, researchers at The University of Texas MD Anderson ...

Barrier proteins in tumors are possible key to immunotherapy success

June 28, 2017
By comparing variations in protein expression in tumor samples from a single melanoma patient, researchers from the Johns Hopkins Bloomberg~Kimmel Institute and the Memorial Sloan-Kettering Cancer Center say their findings ...

Better cancer immunotherapy drugs through X-ray crystallography

May 31, 2017
Immunotherapy drugs to combat cancer have stimulated tremendous excitement among patients and physicians alike. They debuted in 2011, when the U.S. Food and Drug Administration approved ipilimumab (Yervoy) to treat metastatic ...

Absent tumor-suppressors allow melanoma to thwart immunotherapy

March 1, 2017
It's what's missing in the tumor genome, not what's mutated, that thwarts treatment of metastatic melanoma with immune checkpoint blockade drugs, researchers at The University of Texas MD Anderson Cancer Center report in ...

Recommended for you

Fetal gene therapy prevents fatal neurodegenerative disease

July 16, 2018
A fatal neurodegenerative condition known as Gaucher disease can be prevented in mice following fetal gene therapy, finds a new study led by UCL, the KK Women's and Children's Hospital and National University Health System ...

New study finds that fat consumption is the only cause of weight gain

July 13, 2018
Scientists from the University of Aberdeen and the Chinese Academy of Sciences have undertaken the largest study of its kind looking at what components of diet—fat, carbohydrates or protein—caused mice to gain weight.

Basic research in fruit flies leads to potential drug for diseases afflicting millions

July 13, 2018
River blindness and elephantiasis are debilitating diseases caused by parasitic worms that infect as many as 150 million people worldwide. They are among the "neglected tropical diseases" for which better treatments are desperately ...

Light based cochlear implant restores hearing in gerbils

July 12, 2018
A team of researchers with members from a variety of institutions across Germany has developed a new type of cochlear implant—one based on light. In their paper published in the journal Science Translational Medicine, the ...

Researchers discover gene that controls bone-to-fat ratio in bone marrow

July 12, 2018
In an unexpected discovery, UCLA researchers have found that a gene previously known to control human metabolism also controls the equilibrium of bone and fat in bone marrow as well as how an adult stem cell expresses its ...

Intensive care patients' muscles unable to use fats for energy

July 12, 2018
The muscles of people in intensive care are less able to use fats for energy, contributing to extensive loss of muscle mass, finds a new study co-led by UCL, King's College London and Guy's and St Thomas' NHS Foundation Trust.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.