Mechanisms of acquired resistance to immune checkpoint inhibitors

preface

The advent of immune checkpoint inhibitors (ICIs) has rapidly changed the treatment paradigm for many types of cancer, and over the past decade, from the first approval of CTLA-4 inhibitors in metastatic melanoma in 2011, PD-(L)1 inhibitors have become routine treatments
for more than 20 different cancer indications.

This dramatic shift is driven in large part by the unprecedented durability of remission brought about by ICI, and the response can last for years
, even without continued treatment.
However, with the exception of patients with certain diseases (e.
g.
, melanoma, Merkel cells, Hodgkin lymphoma, MSI-H tumors) who have a high response rate (40%−70%) to single-agent PD-1 blockade, the response rate for most other cancer indications is only 10–25%.

In addition, disease may eventually progress
even in patients who initially respond to ICIs.

Resistance to ICIs is divided into two broad categories: 1) primary resistance, which usually refers to patients who do not respond at all but progress rapidly or eventually to ICIs; 2) Acquired resistance, which refers to a period of initial response to treatment followed by eventual disease progression
.

In response to current primary resistance, people often use combination therapy to expand the response population
.
For example, in the combination of lung, breast and gastric cancer ICIs with chemotherapy, as well as multi-target TKIs in RCC and FGFR inhibitors for bladder cancer
.
In addition, predictive biomarkers for initial ICI responses have been extensively studied
.
PD-L1 expression, tumor mutation burden, tumor-infiltrating lymphocytes (TILs), or related gene expression characteristics have been explored as potential predictors, and various other markers are currently being studied
.
Conversely, there are currently no approved treatments to circumvent or reverse acquired resistance, and there is little
research on the characteristics or mechanisms of acquired resistance in ICIs.

Incidence of ICI-acquired resistance

The study pooled data on acquired resistance for ICI in different oncology clinical studies, and it became clear that rates of acquired resistance manifested differently
across multiple disease types.

More generally, there appears to be an inverse relationship
between the total response rate of PD-1 inhibitors and the frequency of responder acquired resistance across tumor types.

Mechanisms of ICI-acquired resistance

Although many cases have uncertain or unknown mechanisms, the resistance mechanisms of ICI can be broadly divided into the following categories: 1) defects in antigen presentation mechanisms; 2) IFN-γ signal path defects; 3) loss of neoantigens; 4) tumor-mediated immunosuppression; 5) Other suppression checkpoints
.

Defects in the mechanism of antigen presentation

Activation of T cell-mediated immunity relies on the recognition of antigens on the major histocompatibility complex (MHC) of antigen-presenting cells, and β-2-microglobulin (B2M) is a key gene
responsible for stabilizing MHC class 1 molecules on the cell surface and promoting antigenic peptide loading.
B2M loss-of-function mutations can lead to MHC I deletion, causing tumors to evade immune system surveillance
.
In addition, there are many other unknown genes or cytokines that may regulate MHC1 expression, thereby affecting resistance to ICI
.

IFN-γ signal path defects

Effector T cells secrete IFN-γ trigger the signaling cascade of tumor cells through the JAK-STAT pathway, mediate MHCI.
and PD-L1 expression, and can induce tumor cell death
through multiple pathways.
In this pathway, the critical first step is activation of receptor-associated kinases JAK1 and JAK2 via the binding of IFN-γ to heterodimer IFNGR1/IFNGR2
.
Recent clinical studies have reported cases of JAK1 or JAK2 inactivated mutations that may have contributed to the progression
of ICI drug resistance.

Neoantigens are lost

Neoantigen-specific T cells may be a key driver of
ICIs' function.
Thus, loss of somatic mutations encoding tumor-specific neoantigens through clonal selection, epigenetic inhibition, or copy number loss may lead to subsequent immune evasion and clinical progression
.

Tumor-mediated immunosuppression

In preclinical models, the deletion of the tumor suppressor gene PTEN, which plays a key role in the regulation of PI3K activity, increased the expression of immunosuppressive cytokines and decreased the expression of T cell effector factor IFN-γ, resulting in inhibition of T cell-mediated infiltration and immunity
.
Loss
of PTEN has also been observed in cases of acquired resistance.

Similar to PTEN loss, WNT-β-catenin activity is associated with immunosuppressive cytokine production, alteration of dendritic cell activation, promotion of regulatory T cells, and lack of T cell infiltration in melanoma, supporting the role
of β-catenin in ICI resistance.

Other suppression checkpoints

Several reports describe upregulated expression of other T cell checkpoints, including TIM3, LAG3, and VISTA,
in acquired resistance.
Although these checkpoints may be functionally associated with T cell failure and end-stage dysfunction in some cases, they may also be associated with
T cell activation.
Therefore, additional data may be needed to understand the functional T cell states in these examples and ultimately the contribution
to acquired resistance.

Challenges in the study of the mechanisms of ICI acquired drug resistance

There are many challenges to studying the mechanisms of immunotherapy-acquired resistance, the main ones including:

1.
Lack of uniform criteria for definerating, classifying and applying acquired resistance;

To analyse and interpret the results of multiple studies, a clear and consistent framework
for defining acquired resistance should be established.
For example, in EGFR-mutant lung cancer, relatively simple but specific guidelines have been developed to define patients
with acquired drug resistance.
The prescribed EGFR criteria should have 1) documented initial objective response to treatment or significant and durable (greater than 6 months) clinical benefit; and 2) systemic progression
of the disease during the last 30 days of ongoing treatment with EGFR-TKI.
These criteria may seem simple and self-evident, but they do help to maintain consistency in assessing the resistance and mechanisms of new treatments
.
There is currently no such uniform definition
of acquired resistance to immunotherapy.

2.
Difficulty in obtaining the best tumor sample for analysis;

The response to ICI is lower than with molecularly targeted therapy, and the occurrence of acquired resistance to ICI is more specific
.
For example, in EGFR-mutant lung cancer, about 80% of patients will respond initially to osimertinib, and almost all responders will eventually develop acquired resistance
.
In this case, routine collection of pre-treatment tissue is reasonably effective
.

However, for ICIs, the proportion of patients who are initially sensitive to treatment is much smaller, and the development of acquired resistance is variable in those who do respond
.
Therefore, in studies of particular interest in acquired resistance, it is
very inefficient to collect tissue from all patients at baseline.
Overall, the more unpredictable nature of acquired resistance to ICIs makes it difficult
to design and execute successful relevant studies.

3.
Lack of routine and effective tools to comprehensively explore and discover the mechanism of tumor immune drug resistance;

In targeted therapy analyses, the use of a large number of next-generation DNA and RNA sequencing has successfully identified the main drivers of acquired drug resistance
.
However, also focusing on sequencing large amounts of DNA and RNA from tumor samples, studies of resistance to ICIs have found only a limited number of acquired genetic alterations
.
Conversely, resistance to ICI can be more subtle, dynamic, and complex, involving at least three interactions (host, tumor, tumor microenvironment) and two components (intratumor and systemic), requiring higher-resolution studies
of genetics, functional status, and spatial connections between tumors and immune cells.

brief summary

Acquired resistance to ICI is a common clinical phenotype, and the study of its mechanism is hampered by many obstacles and relatively little
research.
More effective treatment strategies
can only be obtained through a deep understanding of basic biology that allows for the precise deployment of immunotherapy methods other than immune checkpoint inhibitors.
This requires a concerted effort to overcome barriers to better understanding
the intrinsic biology of acquired anti-ICI.
This advance will ultimately lead to the development of more rational drugs and cell therapies in the future to prevent, circumvent or reverse resistance to ICI
.